In addition to the direct toxicity, there is an autoantibody syndrome directed against HMGCo-A reductase, which may be induced by statins (of any type) or occur spontaneously and may cause necrotizing myopathy as discussed in an earlier section and as reviewed by Mammen.
The mechanism of directly toxic muscle damage is not well understood, but it is likely that inherent enzymatic defects are present in a proportion of the severe cases (see the brief review by Farmer) and that others are due to the aforementioned autoimmune process. A novel insight derived from genome-wide screening has been that variants in a gene (SLCO1B1) that codes for an organic anion-transporting polypeptide confers a risk of statin myopathy (4.5-fold for a heterozygous state and 17 times for the homozygous state; see the study by The SEARCH
Collaborative Group). In addition, the chronic use of statin drugs reduces levels of both ubiquinone and small guanosine triphosphate (GTP)–binding proteins, also plausible factors in statin-induced muscle toxicity.
A clinical problem arises when the CK level is elevated, but the patient taking one of these medications has no muscular symptoms. It has been our general practice to continue the medication if the elevation of CK is in the low range and does not rise over time, and if the medication is considered necessary. If alternative and safe means of lowering the lipid level are available, they should be tried in lieu of a statin, but each patient’s circumstances differ. In a small series, Phillips and colleagues have called attention to a similarly vexing and not uncommon problem: myopathic symptoms such as muscle stiffness, tenderness, and weakness with normal CK concentrations in patients taking a drug in this class. A trial of discontinuing the medication might be appropriate. Finally, we have encountered a number of patients whose CK levels have remained high for months or longer after the medications have been stopped. In a few, CK elevations have remained over years, but we have had no way to ensure that the test was not abnormal before taking the statin. Noted in
Chap. 43 is a polyneuropathy in which statin drugs have been very tentatively implicated.
As a rule, statins should be discontinued if the muscle disorder is serious. Treatment of the immune type of myopathy is complex as the syndrome may persist after discontinuation of the drug. In some instances, discontinuation is followed by spontaneous improvement but others may require glucocorticoids administration or an immunosuppressive agent such as mycophenylate or azathioprine. If there is no response, intravenous immunoglobulin or rituximab may be tried. These approaches have been reviewed by Mammen but there have not been adequate trials to determine the best course of action.
This condition is included here as much for its curious histopathologic features as for its clinical interest. The drug, used widely in the treatment of gout, often gives rise to a mild subacute proximal muscular weakness but has also produced an acute necrotizing myopathy. Most instances of the latter have occurred in patients with a degree of renal failure, which allows accumulation of the drug (even though the drug is metabolized predominantly by the liver). In rare instances the myopathy has affected the cranial musculature and the diaphragm. Many cases also show clinical or electrophysiologic evidence of a polyneuropathy, as pointed out by Kuncl and colleagues, leading to the term colchicine myoneuropathy. The reflexes are diminished and there is mild distal sensory loss. Rare cases of colchicine-induced hypokalemic periodic paralysis and also of myotonia have been reported.