Mechanisms and assessment of statin‐related muscular adverse effects

Abstract

Statin-associated muscular adverse effects cover a wide range of symptoms, including asymptomatic increase of creatine kinase serum activity and life-threatening rhabdomyolysis. Different underlying pathomechanisms have been proposed. However, a unifying concept of the pathogenesis of statin-related muscular adverse effects has not emerged so far. In this review, we attempt to categorize these mechanisms along three levels. Firstly, among pharmacokinetic factors, it has been shown for some statins that inhibition of cytochrome P450-mediated hepatic biotransformation and hepatic uptake by transporter proteins contribute to an increase of systemic statin concentrations. Secondly, at the myocyte membrane level, cell membrane uptake transporters affect intracellular statin concentrations. Thirdly, at the intracellular level, inhibition of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase results in decreased intracellular concentrations of downstream metabolites (e.g. selenoproteins, ubiquinone, cholesterol) and alteration of gene expression (e.g. ryanodine receptor 3, glycine amidinotransferase). We also review current recommendations for prescribers.

Involvement of Monocarboxylate Transporter 4 Expression in Statin-Induced Cytotoxicity

“…23 Moßhammer et al reported that it is not clear whether MCT4-mediated transport of statins across membranes of myocytes plays a role in myopathy. 24 We found that statin-induced cytotoxicity was associated with intracellular accumulation of statins. 17 We hypothesized that suppression of statin-induced cytotoxicity by MCT4 knockdown is associated with intracellular accumulation of statins.…”

Acute Onset Significant Muscle Weakness in a Patient Awaiting Liver Transplantation: Look for Statins

“…1 The risk factors for statin-induced myopathy include higher age, female gender, viral infection, genetics, co-morbidities (diabetes, renal failure, liver disease), multiple medications, perioperative period, and concomitant therapy with certain medications. [1][2][3] Patients with genetic variants of CYP3A4 or on concomitant medications that inhibit activity of this enzyme may result in higher statin levels and thus have higher risk of statin-induced myopathy. These medications include azole antifungals, cyclosporine, clarithromycin, other lipid lowering agents, protease inhibitors, calcium channel blockers, and amiodarone.…”

“…These medications include azole antifungals, cyclosporine, clarithromycin, other lipid lowering agents, protease inhibitors, calcium channel blockers, and amiodarone. [1][2][3] Alcohol abuse also predisposes to statin-induced myopathy.…”

“…5 Exact mechanism of statin-induced myopathy is not clear; possible mechanisms include CYP3A4, vitamin D deficiency, mitochondrial inhibition, changes in intracellular system (due to cholesterol deficiency), and disruption of calcium metabolism of myocytes. 1,6 Statins should be discontinued if muscle symptoms are intolerable or creatine phosphokinase levels >10 times or in presence of renal impairment. Rhabdomyolysis requires hospital admission and intravenous hydration, urinary alkalization to prevent acute renal failue.…”

“…Role of coenzyme Q10 and vitamin D supplementation has not been shown to be effective conclusively. 1,[7][8][9] Statins are considered safe in cirrhosis and several studies have shown reduction of portal hypertension, lower rates of decompensation, risk of hepatocellular carcinoma, and mortality in patients on statins. [10][11][12] As patients with liver disease are more prone for statin-induced myopathy, statins should be kept in differential diagnosis of muscle-related symptoms in these patients.…”