Updated SLCO1B1–simvastatin guideline provides resources to support clinical implementation
Nathan Seligson (University of South Florida College of Pharmacy PharmD Candidate, Class of 2015)
An updated Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for SLCO1B1 (alternative names include OATP1B1, OATP-C) and simvastatin-induced myopathy was published in June 2014. Although dose recommendations have not changed from the 2012 version, authors provided guidance on use of SLCO1B1 genotype alongside updated clinical recommendations for statin therapy and supplied practice-based resources to support adoption of genotype-guided therapy into the electronic health record in this update.
Muscle toxicities are the most common adverse drug reactions observed with statins. Statin-associated myopathy has been linked to changes in function of the SLCO1B1 transporter, which facilitates hepatic uptake of statins and other compounds. SLCO1B1 variability at rs4149056 (contained within the SLCO1B1 *5, *15, and *17 haplotypes) and resultant changes in SLCO1B1 function have been most closely associated with statin-induced muscle toxicity.
To update the previously published 2012 recommendations, guideline authors conducted a systematic literature review focused on effects of SLCO1B1 polymorphisms and statin-related end points. Clinical recommendations were limited to simvastatin due to high-quality evidence supporting a drug–gene association with simvastatin that has been reproduced in randomized trials and clinical cohorts.
The following simvastatin dose recommendations were provided, with consideration of FDA prescribing limits for simvastatin and potential effects of drug–drug interactions:
- Normal SLCO1B1 function (55%-88% of patients): Use desired starting dose and adjust doses of simvastatin based on disease-specific guidelines.
- Intermediate SLCO1B1 function (11%-36% of patients): Use a lower dose or consider an alternative statin (e.g., pravastatin or rosuvastatin); consider routine creatine kinase monitoring.
- Low SLCO1B1 function (0%-6% of patients): Use a lower dose or consider an alternative statin (e.g., pravastatin or rosuvastatin); consider routine creatine kinase monitoring.
Genotype definitions and example diplotypes associated with the above phenotypes were also included.
Although dosing recommendations remain unchanged since the 2012 release of this guideline, this update provided important guidance on the clinical applications of SLCO1B1 genotype in the context of other recent clinical data and recommendations. Notably, American College of Cardiology/American Heart Association cholesterol guidelines released in 2013 have widely been cited as having the potential to increase the number of patients taking statin medications, and thereby potentially benefiting from SLCO1B1-guided therapy.
Guideline authors also presented an approach to using this genetic information alongside other clinical factors that may influence development of statin-associated muscle toxicity, such as drug–drug interactions and concomitant disease states. In individuals who have an intermediate-or low-function SLCO1B1 phenotype who do not achieve optimal effects with lower doses of simvastatin (e.g., 20 mg), authors recommended considering an “alternate statin based on (i) potency differences (i.e., use a lower dose of a higher potency statin such as atorvastatin, rosuvastatin, or pitavastatin); (ii) drug–drug interactions (e.g., boceprevir, clarithromycin, cyclosporine, strong CYP3A4 inhibitors); and (iii) relevant comorbidities (e.g., trauma, significant renal impairment, post–solid organ transplant, thyroid disease).”
Supplemental material published electronically in conjunction with the guideline provided additional resources to support clinical implementation and adoption of these guidelines within an electronic health record, including a clinical implementation workflow, model for clinical decision support, and sample interpretative text to provide in response to a specific SLCO1B1 test results.
Ramsey LB et al. The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 Update. Clin Pharmacol Ther. 2014. [Epub ahead of print]