ReviewStatin-induced myopathies
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 Cerivastatin was withdrawn from the market by the US Food and Drug Administration (FDA) in 2001 due to reports of rhabdomyolysis, which was associated with cerivastatin-gemfibrozil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
References (51)
- et al.
Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials
J Am Coll Cardiol
(2007) - et al.
Effect of coenzyme Q10 on myopathic symptoms in patients treated with statins
Am J Cardiol
(2007) - et al.
New insights into the pharmacodynamic and pharmacokinetic properties of statins
Pharmacol Ther
(1999) Toward “pain-free” statin prescribing: clinical algorithm for diagnosis and management of myalgia
Mayo Clin Proc
(2008)- et al.
Preventive effects of bicarbonate on cerivastatin- induced apoptosis
Int J Pharm
(2007) - et al.
The role of coenzyme Q10 in statin-associated myopathy: a systematic review
J Am Coll Cardiol
(2007) - et al.
Effects of statins on nitric oxide/cGMP signaling in human umbilical veinendothelial cells
Pharmacol Rep
(2010) - et al.
Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial
Lancet
(2003) - et al.
New insights into mechanisms of statin-associated myotoxicity
Curr Opin Pharmacol
(2008) - et al.
TheSLCO1B1*5 genetic variant is associated with statin-induced side effects
J Am Coll Cardiol
(2009)
Effect of co-enzyme Q10 supplementation on simvastatin-induced myalgia
Am J Cardiol
Myotoxicity associated with lipid-lowering drugs
Curr Opin Rheumatol
Resolution of statin-induced myalgias by correcting vitamin D deficiency
South Med J
Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study
Cardiovasc Drugs Ther
Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy
Pharmacoepidemiol Drug Saf
Statin myopathy: an update
Curr Opin Rheumatol
Statin-induced apoptosis and skeletal myopathy
Am J Physiol Cell Physiol
Neuromuscular symptoms and elevated creatinine kinase after statin withdrawal
N Engl J Med
Colchicine poisoning: the dark side of an ancient drug
Clin Toxicol
3-Hydroxy-3-methylglutaryl co-enzyme A reductase and isoprenylation inhibitors induce apotosis of vascular smooth muscle cells in culture
Circ Res
Benefit versus risk in statin treatment
Am J Cardiol
Outcomes in 45 patients with statin associated myopathy
Arch Intern Med
Evidence-based management of statin myopathy
Curr Atheroscler Rep
Individualising the risks of statins in men and women in England and Wales: population-based cohort study
Heart
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Molecular targets of statins and their potential side effects: Not all the glitter is gold
2022, European Journal of PharmacologyCitation Excerpt :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).
Rhabdomyolysis: A syndrome to be considered
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