Statins are among the most commonly prescribed drugs in the world to treat hypercholesterolemia and prevent cardiovascular diseases. They effectively lower cholesterol levels by inhibiting the HMG-CoA reductase, the rate limiting enzyme involved in cholesterol formation. Though well tolerated in general, statins can lead to myopathy with symptoms ranging from mild muscle pain to fatal rhabdomyolysis, especially when they are administered at higher doses and with certain other medications. A common coding SNP, rs4149056, in SLCO1B1 gene has been significant associated with marked increase in systemic exposure to simvastatin and risk of muscle toxicity. The overall effect size and significance of this association were striking for simvastatin with an odds ratio for myopathy of 4.5 (95% CI, 2.6 to 7.7) per copy of the C allele and 16.9 (95% CI, 4.7 to 61.1) among CC homozygotes as compared with the TT genotype (PMID:18650507).
The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published the clinical dosing guideline for SLCO1B1 genotype and simvastatin dosing in Journal Clinical pharmacology & Therapeutics. This guideline explores the relationship between rs4149056 (c.521T>C, p.V174A, SLCO1B1*5) and clinical outcome for all statins. Given that the evidence linking myopathy to rs4149056 in SLCO1B1 is more compelling for simvastatin than for any other statin, this guideline presents dosing recommendations for simvastatin only. This guideline represents the 6th publication from CPIC. All CPIC guidelines are simultaneously published and updated on PharmGKB.
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