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Key Points

  • Disease summary:

    • Statins may cause a series of musculoskeletal and neuromuscular disturbances and diseases, including rhabdomyolysis and mild serum creatine kinase (CK) elevations. Genetic factors have been associated with an increased risk of statin-induced myopathy.

    • Statins or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are widely prescribed because of their cardiovascular benefits. Statins are well tolerated by most patients at low starting dosages but can produce statin-induced neuromyopathy and their usage is ultimately limited by toxicity.

    • The American College of Cardiology (ACC)/American Heart Association (AHA)/National Heart, Lung, and Blood Institute (NHLBI) definitions and terminology are widely used in the literature and therefore used here. They have defined four syndromes:

      • Statin myopathy (any muscle complaints related to statins)

      • Myalgia (muscle complaints without serum CK elevation)

      • Myositis (muscle complaints with CK elevation >10 ULN [upper limit of normal])

      • Rhabdomyolysis (CK activity >10-fold ULN with an elevated creatinine level consistent with brown urine and urinary myoglobin)

    • Muscle complaints encompass aches, cramps, pain, tenderness, weakness, fatigue, and heaviness and are broadly categorized as neuromuscular side effects (NMSEs).

    • NMSE occur in approximately 10% of patients during high-dose therapy, affecting compliance to therapy. NMSEs vary in extent among drugs and from patient to patient.

    • Increased serum CK activity provides the predominant means for assessing the degree of muscle injury, with elevation of CK activity to greater than 10-fold ULN suggested as indicating severe statin-induced neuromyopathy. Elevation of CK to greater than fourfold ULN with statin therapy may warrant testing for underlying metabolic muscle disease. However, serum CK activity correlates poorly with the more common and less severe NMSE, can be normal in patients with NMSE, and is not an effective clinical marker for common NMSE.

  • Differential diagnosis:

    • Muscle pain can be caused by bursitis, myofascial pain, muscle strain, osteoarthritis, radiculopathy, and tendonitis. Other etiologies for muscle complaints or an increased CK level are increased physical activity, trauma, falls, accidents, seizure, shaking chills, hypothyroidism, viral infections, carbon monoxide poisoning, polymyositis, dermatomyositis, alcohol abuse, and drug abuse (cocaine, amphetamines, heroin, or phencyclidine [PCP]).

  • Monogenic forms:

    • No single gene cause of NMSE is known to exist.

  • Family history:

    • One-third of the patients with myopathy have family members who also experienced symptoms associated with lipid-lowering drugs. The presence of family history almost doubles the risk of the adverse reaction.

  • Twin studies:

    • None available.

  • Environmental factors:

    • Physical exercise, addition of a new drug, or paradoxically, rest, or assuming the lying position may trigger symptoms. The disparate nature of these factors suggests more than one pathophysiology.

  • Genome-wide associations:

    • To date there exist two published genome wide studies of statin response. Severe statin myopathy has been strongly associated with the SLCO1B1 *5 variant.

  • Pharmacogenomics:

    • Statin efficacy (low-density lipoprotein-cholesterol [LDL-C] lowering, prevention of major adverse cardiovascular events) and the safety factors of NMSE and myositis strongly influence patient drug selection. Emerging studies are focused on ...

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