Risk Factors and Drug Interactions Predisposing to Statin-Induced Myopathy

Abstract

HMG-CoA reductase inhibitors ('statins') represent the most effective and widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, a critical therapeutic target for primary and secondary prevention of cardiovascular atherosclerotic disease. In the face of the established lipid lowering and the emerging pleiotropic properties of statins, the patient population suitable for long-term statin treatment is expected to further expand. An overall positive safety and tolerability profile of statins has been established, although adverse events have been reported. Skeletal muscle-related events are the most common adverse events of statin treatment. Statin-induced myopathy can (rarely) manifest with severe and potentially fatal cases of rhabdomyolysis, thus rendering the identification of the underlying predisposing factors critical. The purpose of this review is to summarize the factors that increase the risk of statin-related myopathy. Data from published clinical trials, meta-analyses, postmarketing studies, spontaneous report systems and case reports for rare effects were reviewed. Briefly, the epidemiology, clinical spectrum and molecular mechanisms of statin-associated myopathy are discussed. We further analyse in detail the risk factors that precipitate or increase the likelihood of statin-related myopathy. Individual demographic features, genetic factors and co-morbidities that may account for the significant interindividual variability in the myopathic risk are presented. Physicochemical properties of statins have been implicated in the differential risk of currently marketed statins. Pharmacokinetic interactions with concomitant medications that interfere with statin metabolism and alter their systemic bioavailability are reviewed. Of particular clinical interest in cases of resistant dyslipidaemia is the interaction of statins with other classes of lipid-lowering agents; current data on the relative safety of available combinations are summarized. Finally, we provide an update of current guidelines for the prevention and management of statin myopathy. The identification of patients with an increased proclivity to statin-induced myopathy could allow more cost-effective approaches of monitoring and screening, facilitate targeted prevention of potential complications, and further improve the already overwhelmingly positive benefit-risk ratio of statins.

Drug-drug Interactions of Statins Potentially Leading to Muscle-Related Side Effects in Hospitalized Patients

“…The risk factors for statin-induced muscular disorders include, among others, the associations of drugs that may interact with the statins resulting in elevated serum concentration of the statins [10,[14][15][16][17][18].…”

“…As statins (except pravastatin and rosuvastatin) undergo the CYP3A4 metabolism [17], coadministration with drugs that are either CYP3A4 substrates or inhibitors increases the bioavailability of the statins (simvastatin, lovastatin, atorvastatin and to a lesser extent fluvastatin) by inhibiting the hepatic first-pass metabolism [18]. The concomitant therapy with CYP3A4 substrates/inhibitors was found in up to 30% of the patients prescribed with CYP3A4 metabolized statins in a study performed in the United Kingdom [19].…”

An updated review of interactions of statins with antibacterial and antifungal agents

“…Numerous statins are substrates of CYP450, organic anion-transporting polypeptide (OATP)-1B1/3, and other transporters and metabolizing enzymes [3][4][5].Both simvastatin and lovastatin are prodrugs that require activation to simvastatin acid and lovastatin acid, respectively. Simvastatin and lovastatin are the principal CYP3A4 substrates, followed by atorvastatin [5][6][7][8], while fluvastatin and rosuvastatin is a CYP2C9 substrate [9,10]. Pravastatin, and pitavastatin are not substrates of CYP450 [11,12].…”

Is immunity a mechanism contributing to statin-induced diabetes?

“…It has been argued that the cumulative benefits of statins outweigh the potentially small rise in new onset diabetes or other side effects such as myopathy. 30,31 This is a worthwhile debate for clinical practice; however, it is surprising that a drug class that improves blood lipid profiles and is largely anti-inflammatory does not improve blood glucose control, but can actually worsen it.…”