Statin Muscle Toxicity and Genetic Risk Factors

Giuliana Mombelli

doi:10.4172/2332-0672.1000111

Abstract

Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) can cause skeletal muscle toxicity; the risk of toxicity is elevated by drug interactions and pharmacogenetic factors that increase the concentration of statins in plasma. The genetic basis of statin-related muscle disorders is largely unknown. Statins are substrates for several membrane transporters that may mediate drug interactions. Potent inhibitors of cytochrome P450 (CYP450) especially CYP3A4, can significantly increase the plasma concentrations of the active forms of atorvastatin, lovastatin and simvastatin. Fluvastatin, which is metabolized by CYP2C9, is less prone to pharmacokinetic interactions, while pravastatin and rosuvastatin are not susceptible to any CYP inhibition. OATP1B1 can decrease the hepatic uptake of many statins, as well as the therapeutic index of these agents. Polymorphisms of CYP450 enzymes, SLCO1B1, ABCB1, and COQ2 gene, can induce statin intolerance. This review summarized the principal relations known between statin myotoxicity and genetic risk factors.

Highlights

This review provides an update on alleged genetic risk factors, related to muscular disorder with statins intake
This study provided definitive evidence on the role of the SLCO member 1B1 gene (SLCO1B1) gene system on the occurrence of myalgia/myopathy
The results of this study suggest that, on average, in a population treated with ≥40 mg of simvastatin, only nine people would need to be treated, to result in one individual being intolerant on account of this genotype [33]

Summary

Introduction

Statins are a widely used group of drugs which are effective in reducing cardiovascular risk, largely by reducing low-density lipoprotein cholesterol (LDL-C) concentrations [1]. Tomlinson et al [42] in a recent study of 305 Chinese patients treated with rosuvastatin, reported a significant greater reduction in LDL-C levels associated with the presence of a c.421CC genotype This observation is probably explained by the higher blood concentration of this statin, which increased the myopathy risk observed in Asians [42]. Researchers found, in a study involving 291 patients that two genetic variants (SNP1 and SNP2) in the COQ2 gene (rs6535454 and rs4693075) and 2-SNP haplotype were in higher frequency in subjects with statin myopathy than in statin-tolerant subjects. The odd ratios of statin intolerance were 2.42 in homozygotes for rs6535454, 2.33 in homozygotes for rs4693075 and 2.58 for the haplotype of the two variants [10] (Table 1) This association was confirmed by Puccetti et al [45], which found an odd ratio of rosuvastatin-intolerance of 2.6 in subjects carrying rs4693075, independently from the presence of a SNP in the SLCO1B1 gene.

Findings

Discussion

Conclusions