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Simvastatin response

Synonyms
Zocor response

Summary

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 to reduce cholesterol synthesis. Though well tolerated in general, the most common statin side effect is statin-associated musculoskeletal symptoms (SAMS) which range from myalgia, myopathy to fatal rhabdomyolysis, especially when statins are administered at higher doses and with certain other medications. Genetic variations in genes encoding the statin transporters, SLCO1B1 and ABCG2, and metabolizing enzyme, CYP2C9, have been shown to affect systemic plasma concentrations of statins and are associated with increased risk for SAMS. Guidelines regarding the use of pharmacogenomic tests in dosing for statins have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and are available on the CPIC and PharmGKB websites. The CPIC guideline provides specific therapeutic recommendations for simvastatin, atorvastatin, lovastatin, pravastatin and pitavastatin based on SLCO1B1 phenotype; rosuvastatin based on SLCO1B1 and ABCG2 phenotypes; and fluvastatin based on SLCO1B1 and CYP2C9 phenotypes. It serves as a guide for selecting the most appropriate statin and the optimal dose if pharmacogenetic test results are available. [from PharmGKB]

Available tests

14 tests are in the database for this condition.

Check Related conditions for additional relevant tests.

Clinical tests (14 available)

Molecular Genetics Tests

Genes See tests for all associated and related genes

  • Also known as: HBLRR, LST-1, LST1, OATP-C, OATP1B1, OATP2, OATPC, SLC21A6, SLCO1B1
    Summary: solute carrier organic anion transporter family member 1B1

Therapeutic recommendations

From Medical Genetics Summaries

This section contains excerpted1information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

2023 Statement from the US Food and Drug Administration (FDA):

Warnings and Precautions- Myopathy and Rhabdomyolysis

Simvastatin may cause myopathy and rhabdomyolysis… Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs (including other lipid lowering therapies), and higher simvastatin dosage; Chinese patients on simvastatin may be at higher risk for myopathy…The risk of myopathy is increased by elevated plasma levels of simvastatin and simvastatin acid. The risk is also greater in patients taking an 80 mg daily dosage of simvastatin compared with patients taking lower simvastatin tablets dosages and compared with patients using other statins with similar or greater LDL-C lowering efficacy.

Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis

The concomitant use of strong CYP3A4 inhibitors with simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is required, temporarily suspend simvastatin during the duration of strong CYP3A4 inhibitor treatment. The concomitant use of simvastatin with gemfibrozil, cyclosporine, or danazol is also contraindicated … Simvastatin dosage modifications are recommended for patients taking lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine or ranolazine.

Please review the complete therapeutic recommendations that are located here: (1)

2022 Statement from the Clinical Pharmacogenetics Implementation Consortium (CPIC):

Phenotype: SLCO1B1 decreased function or SLCO1B1 possible decreased function

Implications: Increased simvastatin acid exposure as compared with normal function; increased risk of myopathy.

Dosing recommendation: Prescribe an alternative statin depending on the desired potency (see Figure 1 for recommendations for alternative statins). If simvastatin therapy is warranted, limit dose to <20 mg/day.

Phenotype: SLCO1B1 poor function

Implications: Increased simvastatin acid exposure compared with normal and decreased function; highly increased myopathy risk.

Dosing recommendation: Prescribe an alternative statin depending on the desired potency (see Figure 1 for recommendations for alternative statins)

Please review the complete therapeutic recommendations that are located here: (2)

2020 Summary of recommendations from the Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP)

SLCO1B1 521CC: [simvastatin]

When using simvastatin 80 mg/day, the risk of myopathy is increased 30-fold to 18% and the risk of severe myopathy is increased 48-fold to 12%. When using 40 mg/day, this risk is increased 7-fold to 1% and 11-fold to 0.68% respectively. The gene variation leads to reduced simvastatin transport to the liver, which increases the simvastatin plasma concentration and therefore the risk of side effects.

1. Choose an alternative

Consider any additional risk factors for statin-induced myopathy.

Atorvastatin is affected less severely by the SLCO1B1 gene variation, but is also affected by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Use of atorvastatin is not recommended for patients with additional risk factors for statin-induced myopathy.

Rosuvastatin and pravastatin are influenced to a lesser extent by the SLCO1B1 gene variation. They are also not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem.

Fluvastatin is not significantly influenced by the SLCO1B1 gene variation or CYP3A4 inhibitors.

SLCO1B1 521TC: [simvastatin]

When using simvastatin 80 mg/day, the risk of myopathy is increased 5-fold to 3% for moderately severe to severe myopathy and 1.3% for severe myopathy. When using 40 mg/day, this risk is increased 2.6-fold to 0.39% and 0.17% respectively. The gene variation may lead to reduced simvastatin transport to the liver, which may increase simvastatin plasma concentrations and therefore the risk of side effects.

1. Choose an alternative

Consider any additional risk factors for statin-induced myopathy.

Atorvastatin is affected less severely by the SLCO1B1 gene variation, but is also affected by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem. Use of atorvastatin is not recommended for patients with additional risk factors for statin-induced myopathy.

Rosuvastatin and pravastatin are influenced to a lesser extent by the SLCO1B1 gene variation. They are also not influenced by CYP3A4 inhibitors such as amiodarone, verapamil and diltiazem.

Fluvastatin is not significantly influenced by the SLCO1B1 gene variation or CYP3A4 inhibitors.

2. If an alternative is not an option:

1. Avoid simvastatin doses exceeding 40 mg/day (for example, by adding ezetimibe)a

2. Advise the patient to report muscle symptoms. a

Please review the complete therapeutic recommendations that are located here: (3) a Note that minor variations in wording versus the cited guidelines are included here based on personal communication from DPWG.

1 The FDA has distinct labels for specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug. Certain terms, genes and genetic variants may be corrected in accordance with nomenclature standards, where necessary. We have given the full name of abbreviations, shown in square brackets, where necessary.

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