Statin‐associated muscle symptoms: Does the benefit outweigh the risk factor?

Abstract

The treatment of hypercholesterolemia was changed dramatically in 1987, after the introduction of lovastatin, a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase enzyme inhibitor. The use of statin medications has dramatically reduced atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease, stroke, and peripheral artery disease. Statins block HMG-CoA reductase in the mevalonate pathway with downstream effects of reduced hepatic cholesterol synthesis, resulting in increased low-density lipoprotein (LDL) receptors on liver cells, which act to clear cholesterol from the circulation. For primary prevention in patients with very high LDL cholesterol, each 39-mg/dl reduction in LDL by statin therapy reduces the risk of ASCVDrelated morbidity and mortality by about 20%. However, as with all medications, there are risks associated with treatment. Of particular interest to neuromuscular physicians, statins are associated with a spectrum of adverse effects on muscle. These can be mild and self-limited, such as myalgia, which may include a mild, reversible toxic myopathy. The effects can be more severe and debilitating, including rhabdomyolysis or immune-mediated necrotizing myopathy. Fortunately, myalgias are the most common form of statin-associated muscle symptoms (SAMS), but the exact incidence or prevalence is difficult to estimate due to poor definition and the frequency with which myalgias occur in placebo patients. In a meta-analysis of 26 clinical trials, the incidence of muscle symptoms in the statin group vs. placebo was 12.7% and 12.4%, respectively. Defining myalgia incidence via clinical trials is misleading, as most studies have been focused on efficacy and exclude patients that may be more likely to experience side effects, due to other chronic health conditions or medications with statin interactions. Rhabdomyolysis is significantly less common, with one cohort study showing an incidence of rhabdomyolysis requiring hospitalization at 0.44 per 10,000 person-years in the statin-treated group vs. 0 in unexposed person-time. Statinassociated immune-mediated necrotizing myopathy is exceedingly rare, with an estimated incidence of 2 per million per year. Even a more objective measure, such as serum creatine kinase (CK) elevation, may be misleading, as many patients with mild elevations may have no symptoms and those with myalgias may have normal CK. SAMS have a known connection to specific statins, but lipophilic vs. hydrophilic drugs do not seem to differ. Concurrent use of certain medications, such as aspirin, fibrates, cyclosporine, dihydropyridine, and digoxin, increase risk of muscle symptoms in statintreated patients via drug–drug interactions or independent injury to muscle. A 2011 retrospective review showed a lack of association with statin dose, but other studies have shown the opposite. Various medical conditions have been associated with inducing and exacerbating muscle symptoms, including hypothyroidism, neuromuscular and rheumatologic diseases, and vitamin D deficiency. Genetic risk factors are of increasing interest in the prediction of statin intolerance. SLCO1B1, a protein involved in hepatic uptake of statins, and COQ2, involved in the synthesis of coenzyme Q10, have specifically been associated with statin-induced myopathy. The human leukocyte antigen class II allele, DRB1*11:01, is associated with statin-associated immune-mediated necrotizing myopathies. Categories of genes are under evaluation for links to SAMS, including statin metabolism genes, statin transporter proteins, muscle disease mutations, pain perception genes, and vascular receptors. Pathologically, myocyte damage from T-tubule disruption and subsarcolemmal rupture seen on electron microscopy could, in part, be due to the cholesterol-lowering effects of statins and are present even in asymptomatic patients, with normal CK, and after discontinuation of the statin. Many patients who develop SAMS while taking a statin medication can be successfully restarted on treatment and there are methods to manage the adverse effects. Based on the severity of symptoms and level of CK, the patient may try vitamin D Conflict of Interest: None of the authors have any conflict of interest to disclose.