Practical Pearls: Evaluating and Managing Myopathies in Dyslipidemics

Statins prevent atherosclerotic cardiovascular diseases (ASCVD). Hepatic injury (my patients most feared effect) occurs in ≤1 percent and is similar on placebo. Elevated hepatic transaminases typically resolve spontaneously and mostly are a result of dyslipidemia causing hepatosteatosis and/or cholelithiasis.¹

Myopathies are a potential side effect of statins that may be associated with untreated dyslipidemias.^2-5 Myalgias with or without elevated serum creatine kinase levels (ESCKL) — ≤X3-5 the upper limits of normal (ULN) — are common in dyslipidemics without treatment(s). Myositis and rhabdomyolysis are rare but possible complications from statins.

In 8,000 patients in the Expanded Clinical Evaluation of Lovastatin (EXCEL) study,⁵ myopathy or ESCKL in 4,000 patients on lovastatin was similar to 4,000 on placebo. This trial demonstrated that myalgias with or without ESCKL occurred in 30 percent of dyslipidemics on placebo. Thus, myalgias with or without ESCKL occurs in as many as 1/3 of untreated dyslipidemic patients.⁵

These circumstances may lead to discontinuation of statins in patients showing ESCKL, depriving them of ASCVD prevention without unequivocal causality. In my experience, >75 percent of patients discontinued from statins because of myalgia or ESCKL <X3-5 ULN can be safely restarted on the same or a different statin at an equal or lower dosage, if properly diagnosed and managed.

Statin-Related Muscle Symptoms or Injury (Myopathies)
Myopathy describes muscle weakness (not attributed to pain and not necessarily associated with elevated CK). Myalgia refers to muscle symptoms — aches or weakness — with or without ESCKL. Myositis denotes ESCKL with or without muscle symptoms. Rhabdomyolysis indicates symptoms with ESCKL ≥x10ULN, creatinine elevation, and renal failure risk. Myalgias are common with statin use. Severe myositis and severe rhabdomyolysis are far less common (5.0 and 1.6 per 100,000 patient-years, respectively) and appear similar across currently approved doses of the marketed statins. Controlled comparative studies are lacking. The mechanism of statin-induced muscle injury is uncertain.

Muscle biopsies in my dyslipidemic patients at Johns Hopkins Hospital were diagnosed of abnormal mitochondrial structures by electronmicroscopy, referred to in pathology reports as “possible ischemic capilaromyopathy.” ESCKL were documented after controlled physical activity in non-treated dyslipidemics and they were exacerbated after lovastatin.^6,7

Risk Factors for Statin-Associated Myopathy
Table 1 lists factors increasing the likelihood of statin myopathy. Multiple clinical trials found that the risk of myopathy is dose-dependent. The U.S. Food and Drug Administration (FDA) cautioned about the increased risk of muscle related toxicity from, and proscribed the use of 80 mg dose of simvastatin.

Placebo-controlled trials found the incidence of statin-related myopathy from ≤40 mg/day is similar to placebo. Dosages >40 mg/day of simvastatin are the riskiest.

Management strategies for patients with muscle symptoms and/or ESCKL
•   Discontinue statin administration if used in primary prevention and lower the dosage to one half if used in secondary prevention.

•   Discontinue statin use if symptoms or ESCKL are >X3-5 ULN.

•   Give patient detailed instructions on how to keep diaries of time of the day as well as duration and site(s) of symptoms every day while the statin is discontinued or decreased. Also, keep a diary (type, time, and duration) of all physical activities and symptoms.

•   Measure CKL daily, continue modified regimen if unchanged; measure CKL weekly until significantly decreased (≥X3 ULN).

•   Discontinue statin permanently if ESCKL ≥X10 ULN and there is an absence of factors in Table 1.

•   Patients should keep daily records of muscle symptoms while off and on statin to compare with medical proffesional to determine presence, absense, or degree of causality.

•   Measure vitamin D levels in blood and give supplemental therapy if indicated.

Prevention of Statin- and Non-Statin- Related Myopathies, Myalgias, and/or ESCKL
•   Instruct patients to abstain from aerobic or strenuous physical activity (moving furniture, ball games, etc.) for 48 hours preceding their visit to lipid clinics.

•   Use the lowest dose of statin that allows the patient to reach goals and/or combine the statin with bile acid sequestrants or ezetimibe to add greater efficacy without myotoxicity.

Summary of Frequent Interactions with Statin Metabolism
Risk of muscle-related side effects increases when statins are taken with medications or foods known to inhibit CYP3A4/CYP2C9/CYP219 metabolism. Serum levels of atorvastatin, simvastatin, and lovastatin may increase from four-to six-fold if given in conjunction with erythromycins or verapamil, and from 10- to 20-fold with azole antifungals. Cyclosporine, simvastatin, lovastatin, and rosuvastatin levels have been reported to increase while a patient is taking gemfibrozil. Rhabdomyolysis was 0.44 per 10,000 patient-years with statin monotherapy versus 5.98 when statins were combined with gemfibrozil. Grapefruit juice (>1 quart per day) inhibits statin metabolism. Protease inhibitors can accomplish the same. Pravastatin, rosuvastatin, pitavastatin, and fluvastatin — in increasing order of frequency — have the lowest drug interaction potential.

Patients who have disease states or are taking concomitant medications known to independently cause myalgias are more likely to experience muscle injury when statin therapy is initiated. Untreated hypothyroidism and alcohol abuse may predispose patients to myopathic symptoms from statin therapy. Some fibrates often used in patients taking statins have their own associated risks of myopathy, although these appear to be rare and have not been confirmed by large, well-designed studies. There is no supportive evidence for the hypothesis that lipophilic statins (e.g., lovastatin, simvastatin, atorvastatin), which penetrate muscle fibers more easily, are more likely to cause myopathy or any other side effects from statins than the hydrophilic statins (e.g. pravastatin, rosuvastatin).

Disclosure statement: Dr. Dujovne has no disclosures to report.

References are listed on page 36 of the PDF.