Statin myopathy: A common dilemma not reflected in clinical trials

Statins can unveil underlying musculoskeletal disorders

Ample observational data suggest that statin therapy unveils underlying muscle disorders, perhaps by adding yet another metabolic stress to patients with abnormal metabolism. We see many patients whose primary diagnosis is not statin toxicity but an underlying metabolic muscle disorder, the symptoms of which have been made worse by statin therapy. The most common diagnoses that may simulate statin muscle toxicity are listed in Table 2.

Atypical complaints require us to search for an alternate diagnosis before dismissing them as not statin-induced.

Previous episodes of myoglobinuria (dark urine after exertion) would raise the possibility of a metabolic myopathy. Frequent muscle cramps raise the possibility of a metabolic myopathy or motor neuron disease.

Asymmetric pain or pain involving joints and ligaments is less likely to be statin-related but in our experience occasionally occurs.

Some patients with underlying degenerative arthritis or tendinitis repeatedly develop worsening symptoms each time they take statins, perhaps because muscle weakness exacerbates the arthropathy or tendinopathy.⁴⁵

Although statin-related muscle complaints are almost always symmetric, many patients with underlying peripheral vascular disease have asymmetric pain in the limb with poor vascular supply; the pain is reproducible by statin rechallenge.

In our experience, many patients whose chronic low back pain is due to a lumbar radiculopathy experience exacerbations of that pain whenever they start statins.

Weakness preceding the use of the statins or a family history of neuromuscular disorders may indicate a neurodegenerative disorder and warrants consideration of early neurological consultation.

Although these rules are not absolute, they are helpful in the initial evaluation, which must exclude alternative diagnoses.

Is the patient a vegetarian? A drinker? Taking supplements?

Taking a careful history of diet and supplement use is important to find exposures that may increase the risk of statin-related muscle complaints. Vegetarians may develop carnitine or vitamin B₁₂ deficiencies. Alcohol and vitamin E and other supplements are occasional causes of muscle symptoms falsely attributed to statin therapy. It is also important to remember that red yeast rice contains lovastatin, which can exacerbate myopathy, especially when taken in conjunction with another statin.

Physical examination

The examination of patients with possible statin-induced myopathy begins with a general assessment for signs of hypothyroidism or excess alcohol consumption.

Ankle-brachial indices are used to exclude significant peripheral vascular disease.

The musculoskeletal examination focuses on muscle atrophy, tone, and strength but also excludes tendinopathies, arthropathies, and myofascial pain syndromes, which are often confused with muscle pain.

We conduct quantitative dynamometry, measuring handgrip with a Jamar dynamometer and hip abduction with a Nicholas Manual Muscle Tester. Precise dynamometric measurements are tracked at subsequent visits and are helpful in following recovery from myopathy as well as in tracking strength during subsequent statin rechallenges.

We routinely look for hyperreflexia, fasciculations, extensor-plantar responses, and decreased heel-to-shin movement, which would suggest myelopathy. Reflexes and a sensory examination including vibration and temperature sensation help exclude radiculopathy and peripheral neuropathy.

Laboratory evaluation

In every patient with possibly statin myopathy, the primary care physician should measure:

• The serum CK level (preferably more than 72 hours after exercise)
• The 25-hydroxy vitamin level
• The thyroid-stimulating hormone level.

Further laboratory evaluation depends on the findings and will often be directed by subspecialists. For example, we assess the sedimentation rate, anti-Ro and anti-La antibodies, and the myositis panel in patients with elevated CK whose other findings suggest an autoimmune or inflammatory process. We test serum carnitine levels (free, total, and esterified), fasting serum lactate levels, and serum cortisol in those with findings suggestive of metabolic myopathy. We order electromyography and nerve conduction studies in patients with possible myelopathy, peripheral neuropathy, or inflammatory myopathy.

Ultimately, a muscle biopsy may be necessary to exclude inflammatory or necrotizing myopathies in patients whose CK remains elevated despite withdrawal of statins. It may also be helpful when other findings suggest a metabolic myopathy. When a biopsy is needed, magnetic resonance imaging of the affected limb may identify an affected muscle for biopsy.

MANAGEMENT

Reassess the lipid goal

Figure 2 outlines the clinical settings associated with statin-induced myopathy, and provides an algorithmic approach for managing it.

If the source of a complaint remains unclear after challenge and rechallenge with alternate statins, we generally recommend restarting therapy and trying to achieve the LDL-C goal. If the workup suggests a neurologic or rheumatolic etiology, a referral to a specialist is indicated. However, if the evaluation leads to a diagnosis of statin-induced myopathy, the next task is to reassess the lipid treatment goals.

The Adult Treatment Panel (ATP) III guidelines should be used to assess the patient’s risk of having major coronary heart disease in the next 10 years, and to determine appropriate LDL-C goals.⁴⁶ Some patients with suspected toxicity may have been treated to more aggressive LDL-C levels than recommended by these guidelines. The first step in these patients is to reduce or discontinue the unnecessary statin, even if there is no clear evidence of toxicity.

For the rest of patients with suspected toxicity, the decision to discontinue statin therapy must be weighed against the estimated reduction in risk associated with taking a statin medication.

Table 3 lists the large statin efficacy trials^47–58 by baseline risk. We provide the number needed to treat to prevent a major adverse cardiac event in order to facilitate clinician-patient discussions about the magnitude of benefit derived from therapy.