Impact of genetic variation on response to therapy
The SLCO1B1 transporter (also known as OATP1B1 and OATP-C) plays an important role in the transfer of statins from the blood into the liver. Reduced function of this transporter can lead to increased plasma concentrations of statins and an increased risk of statin-related muscle toxicity (SRM) including myalgia, myopathy and rhabdomyolysis.
Many variants have been found in the SLCO1B1 gene. The variant c.521T>C is a loss-of-function variant, which has been found to be associated with an increased risk of SRM. The SmPC for simvastatin includes a special warning and precaution for use stating that homozygous C/C or heterozygous T/C carriers of this variant have an increased risk of simvastatin associated myopathy compared to people with the genotype T/T and high doses should be avoided in homozygous C/C carriers. The c.521T>C variant is contained within SLCO1B1 *5 and *15 allele haplotypes.
The main benefit of pharmacogenomic testing for simvastatin is to identify patients who have a higher potential to experience SRM and to aid drug choice and dose modification.
Testing recommendations
The SmPC for simvastatin states that, where available, genotyping for the presence of the c.521T>C variant should be considered as part of the risk benefit assessment before prescribing high dose (80mg) simvastatin.
Therapeutic recommendations
SLCO1B1 function unknown
- Initiate and titrate according to disease-specific guidelines.
SLCO1B1 increased function
Some examples of SLCO1B1 genotypes include (see note): *14/*14
- Initiate and titrate according to disease-specific guidelines.
SLCO1B1 normal function
Some examples of SLCO1B1 genotypes include (see note): *1/*1, *1/*14, c.521T/T
- Initiate and titrate according to disease-specific guidelines.
SLCO1B1 decreased function
Some examples of SLCO1B1 genotypes include (see note): *1/*5, *1/*15, c.521T/C
- Increased risk of SRM compared to individuals with SLCO1B1 normal function.
- Choose an alternative statin with a lower risk of SRM where possible (see Further information).
- If an alternative statin is not possible, start with a maximum of 10mg daily and titrate slowly according to response. Do not exceed 40mg daily. Avoid using simvastatin in patients taking concomitant medicines known to increase plasma concentrations of simvastatin and/or with additional risk factors for SRM.
- Advise patient on action to take if they experience muscle symptoms.
SLCO1B1 poor function
Some examples of SLCO1B1 genotypes include (see note): *5/*5, *5/*15, *15/*15, c.521C/C
- Greatly increased risk of SRM compared to individuals with SLCO1B1 normal function.
- Avoid simvastatin.
- Choose an alternative statin with a lower risk of SRM (see Further information).
Note: Both the star(*) allele and c.521T>C genotype are provided as examples. Reporting methodology may vary by laboratory.
Further information
Drug interactions
The effects of drug-drug interactions with simvastatin may be more pronounced in people with reduced SLCO1B1 function and are likely to be additive to the impact of genetic variation. Multiple mechanisms may contribute to potential interactions with statins. Drugs, herbal products or other substances that inhibit certain enzymes (e.g. CYP3A4) and/or transporter pathways (e.g. SLCO1B1, BCRP) may increase simvastatin plasma concentrations and may lead to an increased risk of SRM. Consult the SmPC of simvastatin and of all concomitantly used drugs to obtain further information about their potential interactions with simvastatin.
High dose simvastatin
Simvastatin 80mg is generally avoided in UK practice due to the risks of side-effects and drug interactions. The SmPC for simvastatin states that the general risk of myopathy with simvastatin 80mg is ~1% without genetic testing. Based on the results of the SEARCH trial, SLCO1B1 c.521T>C homozygous C/C carriers (poor function) treated with 80 mg have a 15% risk of myopathy within one year, while the risk in heterozygous C/T carriers (decreased function) is 1.5%. The corresponding risk in patients with T/T genotype (normal function) is 0.3%.
Other factors influencing risk of SRM
The risk of SRM is influenced by a variety of factors in addition to genotype. These include dose, age, gender, comorbidities and drug interactions. Additional risk factors for SRM should be considered when prescribing statins.
Patients already on stable and effective statin therapy
The main benefit of pharmacogenomic testing for statins is to aid in medication selection by identifying patients who are more or less likely to experience adverse effects including SRM. For patients who have already been on a stable and effective statin dose for more than 1 year without concerns regarding adverse effects, it is likely to be safe to continue.
Alternative statins in individuals with decreased or poor SLCO1B1 function
Atorvastatin, rosuvastatin, fluvastatin and pravastatin are influenced to a lesser extent by SLCO1B1 variation. See individual drug monographs for further information. Choice of statin should take into account lipid lowering intensity, and local and national statin prescribing guidelines.
References
Clinical Pharmacogenetics Implementation Consortium CPIC® (2022) Guideline for statins and SLCO1B1, ABCG2, and CYP2C9. Available at: https://www.clinpgx.org/guideline/PA166264281 Accessed online 12th February 2026.
Organon Pharma (UK) Ltd (2025) Zocor 40mg Tablets SmPC. Available at: https://www.medicines.org.uk/emc/product/7789/smpc (Accessed online: 12th February 2026).
Wolthuis et al. (2025). Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between SLCO1B1 and statins and CYP2C9 and sulfonylureas. European Journal of Human Genetics, 33(4):413-420. https://doi.org/10.1038/s41431-024-01769-7 Accessed online 12th February 2026.
NHS England (2023) Statin intolerance pathway. Available at: https://www.england.nhs.uk/aac/publication/statin-intolerance-pathway/ Accessed online 27th May 2026.
