Diagnosis and Definitions

No well-accepted, standardized, or Food and Drug Administration diagnostic criterion exists for statin intolerance. The term statin intolerance typically refers to an inability to use statins because of significant symptoms or elevated CK levels, and the major diagnostic challenge is to unambiguously link these to statin use. No specific biomarkers exist. Although some investigators consider a statin withdrawal and rechallenge as the cornerstone of diagnosis, it is often not undertaken (see discussion in “Approach to Patients with Statin Myopathy”).

The term myopathy refers to any disease of the muscle including toxic, acquired, and hereditary disorders. For statin-induced myopathy, the following definitions are adapted from the National Lipid Association, American College of Cardiology/American Heart Association (ACC/AHA), and the Canadian Working Group Consensus. Myalgia refers to having myopathy symptoms but no elevation in CK levels. The symptoms include muscle aches, weakness, cramps, stiffness, or “heaviness” and may mimic flu-like symptoms. Asymptomatic myopathy refers to having no symptoms but a CK elevation that resolves after the statin is stopped. Myositis refers to having myalgias along with CK elevation. Rhabdomyolysis occurs when muscle fibers break down leading to release of muscle fiber contents (myoglobin) into the bloodstream. Diagnosis involves extreme elevations in CK levels (either CK >10,000 U/L or 10-fold higher than the upper limit of normal ) with creatinine elevation, although not all definitions require evidence of renal dysfunction.

No standardized definition is used in clinical trials of therapies for statin-intolerant patients. Some investigators, as well as the ACC/AHA Blood Cholesterol Guidelines committee, divide statin intolerance into either complete (intolerant to any statin at any dose) or partial (intolerant to some statins at some doses). Others broadly divide it into severe or mild: severe cases present with incapacitating muscle pain or weakness, rhabdomyolysis, persistent symptoms after therapy, progressive worsening, CK >4 times the upper limit of normal, or an inability to tolerate lower doses of statins; mild cases present with aches and pains that resolve with cessation of therapy. For clinical trials, a recently proposed definition involves an inability to tolerate at least 1 statin at the starting daily dose and another statin at any dose ( ClinicalTrials.gov identifier: NCT01709513 ).

Hepatotoxicity also results in cessation of statin therapy, albeit rarely. In clinical trials, transaminitis occurs in 0.5% to 3.0% of patients. Most patients who experience liver injury do so within 3 to 4 months after starting therapy. Atorvastatin is mostly associated with cholestatic liver injury, whereas hepatocellular injury is more common with simvastatin. Per the Food and Drug Administration and the ACC/AHA Blood Cholesterol Guidelines committee, baseline measurements of alanine transaminase levels should be performed before initiating statins and, if normal, do not need to be measured again unless symptoms of hepatotoxicity arise. However, unexplained alanine transaminase levels >3 times the upper limit of normal is a contraindication to statin therapy as listed in manufacturer’s prescribing information. In such cases, statin therapy should be avoided or discontinued.

Historical Context

The first case of statin-induced myositis occurred soon after the discovery of statins by Drs. Akira Endo and Masao Kuroda in Japan. They administered high doses of mevastatin to a 17-year-old girl with homozygous familial hypercholesterolemia and noted “a side effect (muscular weakness at the proximal parts of the extremities with a rise of serum creatine phosphokinase, glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase activity).” They also noted “these side effects completely disappeared within 2 weeks after withdrawal of the drug.” With lower doses of the mevastatin, “the side effects were no longer experienced.”

In 1988, the New England Journal of Medicine published the first cases of rhabdomyolysis with statins: 5 cardiac transplant patients experienced rhabdomyolysis after taking lovastatin.

The only statin ever removed from the market, cerivastatin, caused an excess of rhabdomyolysis—10 to 50 times greater than other statins—and death that was dose related and often occurred with concomitant gemfibrozil administration. Cerivastatin interacts with a wide range of cytochrome P450 (CYP) isozymes, affecting drug metabolism and likely predisposing to a variety of drug-drug interactions.

Historical Context

The first case of statin-induced myositis occurred soon after the discovery of statins by Drs. Akira Endo and Masao Kuroda in Japan. They administered high doses of mevastatin to a 17-year-old girl with homozygous familial hypercholesterolemia and noted “a side effect (muscular weakness at the proximal parts of the extremities with a rise of serum creatine phosphokinase, glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase activity).” They also noted “these side effects completely disappeared within 2 weeks after withdrawal of the drug.” With lower doses of the mevastatin, “the side effects were no longer experienced.”

In 1988, the New England Journal of Medicine published the first cases of rhabdomyolysis with statins: 5 cardiac transplant patients experienced rhabdomyolysis after taking lovastatin.

The only statin ever removed from the market, cerivastatin, caused an excess of rhabdomyolysis—10 to 50 times greater than other statins—and death that was dose related and often occurred with concomitant gemfibrozil administration. Cerivastatin interacts with a wide range of cytochrome P450 (CYP) isozymes, affecting drug metabolism and likely predisposing to a variety of drug-drug interactions.

Characteristics

Several findings characterize statin-induced myalgias: they occur symmetrically, involving large and proximal muscle groups, especially the legs ; they begin within 6 months of drug initiation but can occur at any time during the course of statin administration ; and they improve promptly after drug termination, but can take up to 3 months to resolve completely.

Occasionally, muscle symptoms or elevated CK persist after drug discontinuation. Such cases should prompt for investigation of both common myopathies (e.g., polymyositis and polymyalgia rheumatica) and underlying metabolic muscle disorders. Of patients with myopathy severe enough to warrant a muscle biopsy, roughly 10% have genetic variants for triggerable metabolic muscle diseases such as heterozygous myophosphorylase deficiency, homozygous myophosphorylase deficiency (McArdle disease), heterozygous carnitine palmitoyltransferase II ( CPT2 ) deficiency, Pompe disease and malignant hyperthermia due to ryanodine receptor ( RYR1 ) mutations.

Risk Factors

Clinical trials and observational studies identify several risk factors for statin-induced myopathy ( Table 1 ): advanced age, female sex, small body frame and frailty, multisystem disease, chronic kidney disease, hypothyroidism, alcoholism, grapefruit juice consumption, major surgery or perioperative period, excessive physical activity, history of myopathy while receiving another lipid-lowering therapy, history of CK elevation, unexplained cramps, family history of myopathy, family history of statin-induced myopathy and antidepressant use. Additional drug-related risk factors include high-dose statin therapy and interaction with concomitant drugs (see Table 2 ). Of all these risk factors, myopathy correlates most closely with the dose of statin.

Race also factor into the risk for development of statin myopathy. In 2005, the Food and Drug Administration issued a public advisory for the use of rosuvastatin in Asians. Pharmacokinetic studies found rosuvastatin drug levels elevated approximately twofold in Asian Americans compared with a Caucasian control group, prompting a label change that now recommends 5 mg as the starting dose for Asians.