Elsevier

Pharmacological Reports

Volume 63, Issue 4, July–August 2011, Pages 859-866
Pharmacological Reports

Review
Statin-induced myopathies

https://doi.org/10.1016/S1734-1140(11)70601-6Get rights and content

Abstract

Statins are considered to be safe, well tolerated and the most efficient drugs for the treatment of hypercholesterolemia, one of the main risk factor for atherosclerosis, and therefore they are frequently prescribed medications. The most severe adverse effect of statins is myotoxicity, in the form of myopathy, myalgia, myositis or rhabdomyolysis. Clinical trials commonly define statin toxicity as myalgia or muscle weakness with creatine kinase (CK) levels greater than 10 times the normal upper limit. Rhabdomyolysis is the most severe adverse effect of statins, which may result in acute renal failure, disseminated intravascular coagulation and death. The exact pathophysiology of statin-induced myopathy is not fully known. Multiple pathophysiological mechanisms may contribute to statin myotoxicity. This review focuses on a number of them. The prevention of statin-related myopathy involves using the lowest statin dose required to achieve therapeutic goals and avoiding polytherapy with drugs known to increase systemic exposure and myopathy risk. Currently, the only effective treatment of statin-induced myopathy is the discontinuation of statin use in patients affected by muscle aches, pains and elevated CK levels.

Introduction

Statins are considered to be safe, well tolerated and the most efficient drugs for the treatment of hypercholesterolemia, one of the main risk factor for atherosclerosis, and therefore they are frequently prescribed medications [21, 23].

The 4S study [39] published in 1994 showed that chronic intake of simvastatin significantly reduced mortality in individuals with hypercholesterolemia and coronary heart disease. These data triggered a great interest in statins. Subsequent studies highlighted the benefits of statin treatment in primary and secondary prevention for coronary heart disease and in individuals with normal cholesterol levels [16, 25, 40]. Currently, the role of statins in reducing the risk of cardiovascular disease is well established [39].

According to the World Health Organization definition, adverse drug reactions are any noxious, unintended and undesired effects of a drug, which occur at doses used in humans for prophylaxis, diagnosis or therapy. This definition excludes therapeutic failures, intentional and accidental overdose and drug abuse, adverse events due to errors in drug administration or noncompliance (taking more or less of a drug than the prescribed amount) [50].

Adverse drug reactions account for approximately 5% of all hospital admissions and 5% of all fatalities [19, 27]. Cerivastatin was withdrawn from the market by the US Food and Drug Administration (FDA) in 2001 due to reports of rhabdomyolysis, which was associated with cerivastatin-gemfibrozil combination therapy [43].

Section snippets

Myotoxicity – definition and incidence

The most severe adverse effect of statin therapy is myotoxicity. Its various forms include myopathy, myalgia, myositis and rhabdomyolysis [19] (Tab. 1).

The number of muscle complaint incidences varies between studies mainly due to the contradictory definitions of myopathy. According to the US National Lipid Association Statin Safety Assessment Task Force [33], a meta-analysis of 21 clinical trials providing 180,000 person-years of follow-up found that myopathy, defined by muscle symptoms and

Myalgias

Symptoms of statin-induced myopathy include any combination of myalgias, muscle tenderness or weakness. Patients describe an aching or cramping sensation in their muscles. Tendon pain and nocturnal leg cramps may also occur [23, 42]. Muscle symptoms are typically more widespread and intense with exercise, and athletes are frequently intolerant to statin therapy. Muscle weakness is usually proximal, but some patients describe difficulty opening jars and snapping their fingers [42]. The incidence

Raised creatine kinase levels

Clinical trials commonly define statin-induced toxicity as myalgia or muscle weakness with CK levels greater than 10 times the ULN [10, 42, 47]. In the meta-analysis of 16 studies including 41,457 patients by Kashani et al. [20], CK elevation was not significantly higher in patients treated with statins [20]. In a cross-sectional study of 136 patients with lipid-lowering drug-induced myopathies, Vladutiu et al. [48] reported a higher prevalence of underlying metabolic muscle diseases than

Rhabdomyolysis

Rhabdomyolysis is the most severe adverse effect of statins, which may result in acute renal failure, disseminated intravascular coagulation and death.

According to Guyton [13], the mortality risk from rhabdomyolysis (estimated to be 0.3 per 100,000 person-years) is outweighed by the reduction in mortality by all causes observed in statin trials (360/100,000 person-years). According to the FDA, the rate of fatal rhabdomyolysis is 0.15 per 1 million statin prescriptions (ranging from 0 with

Mechanisms of myotoxicity

The exact pathophysiology of statin myopathy is not fully known. Multiple pathophysiological mechanisms may contribute to statin myotoxicity. This review focuses on some of them (Tab. 2).

Risk factors

The prevention of statin-related myopathy involves using the lowest statin dose required to achieve therapeutic goals and avoiding polytherapy with drugs known to increase systemic exposure and myopathy risk [18].

The identification of patients with an elevated risk of statin-induced myopathy is substantial. On the basis of the PRIMO study, the major risk factors for muscle symptoms during high-dosage statin therapy are a personal or family history of muscle symptoms, cramps, hypothyroidism and

Conclusions

The above-mentioned mechanisms of statin-induced myotoxicity are hypothetical, and most of them are based on in vitro and experimental studies on animals. Statins were shown to have pleiotropic effects [44]; however, more studies on myotoxicity are required to understand these mechanisms in humans. Once understood, it will be easier to develop preventative measures or to invent a new generation of lipid lowering medications. Currently, the only effective treatment of statin-induced myopathy is

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      Of note, in 2001, cerivastatin was withdrawn from the market due to a much higher incidence of rhabdomyolysis compared to any other statin. Statins metabolized by the CYP3A4 enzyme are much more likely to cause myotoxicity and/or rhabdomyolysis due to greater chances of drug-drug interactions (Tomaszewski et al., 2011). Other risk factors that increase the likelihood and severity of statin-induced myotoxicity include female gender, age over 80, other underlying neuromuscular diseases, and alcohol abuse (Thompson et al., 2016).

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