Clinical Information

The most common adverse drug reaction associated with statins is skeletal muscle toxicity, which can include myalgia (with and without elevated creatine kinase levels), muscle weakness, muscle cramps, myositis, and rhabdomyolysis.(1) Rhabdomyolysis, while rare, is of clinical concern because of the risk for death as a result of cardiac arrhythmia, renal failure, and disseminated intravascular coagulation. While the underlying causes of statin-associated myopathy are not known, several hypotheses have been formulated, including those related to the biochemical pathway of cholesterol synthesis inhibition and statin metabolism.

SLCO1B1 encodes the organic anion-transporting polypeptide 1B1 (OATP1B1) influx transporter located on the basolateral membrane of hepatocytes. OATP1B1 facilitates the hepatic uptake of statins as well as other endogenous compounds (eg, bilirubin). Changes in the activity of this transporter (eg, through genetic variations or drug-drug interactions) can increase the severity of statin-associated myopathy (ie, statin intolerance).(2)

SLCO1B1 rs4149056 (c.521T>C, p.V174A), which is found in *5, *15, and *17, interferes with localization of the transporter to the plasma membrane and can lead to increased systemic statin concentrations.(3-4) All statins are substrates of OATP1B1, but the association of SLCO1B1 c.521T>C with statin intolerance varies depending on statin and dose and is most pronounced with higher doses of simvastatin therapy. A case-control study of simvastatin-induced myopathy observed an odds ratio (OR) for myopathy of 4.5 for *5 heterozygotes and 16.9 for *5 homozygotes (compared to individuals who did not carry *5) among patients receiving high-dose (80 mg/day) simvastatin therapy.(4) A dose relationship was also demonstrated in a replication cohort of patients taking 40 mg/day simvastatin with a relative risk of 2.6 per copy of the *5 allele. While the SLCO1B1 c.521T>C genotype has also been shown to affect systemic exposure of other statins (eg, atorvastatin, pravastatin, rosuvastatin) in addition to simvastatin,(3) there is less evidence demonstrating a clinical association between the SLCO1B1 genotype and myopathy with statins other than simvastatin.(2)

Frequency of the SLCO1B1 alleles varies across different racial and ethnic groups.