Simvastatin

Simvastatin (brand name Zocor) is a commonly prescribed statin medication used to lower cholesterol levels in the blood.

It is indicated for the treatment of hypercholesterolemia and prevention of cardiovascular events by reducing low-density lipoprotein (LDL) cholesterol. Clinical trials have demonstrated its benefit in decreasing heart attack and stroke risk.

The mechanism of action involves competitive inhibition of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, leading to decreased hepatic cholesterol production and increased clearance of circulating LDL cholesterol.

Simvastatin exposure and efficacy are influenced by the SLCO1B1 gene, which encodes the organic anion-transporting polypeptide 1B1 (OATP1B1) transporter in hepatocytes.

OATP1B1 mediates the uptake of simvastatin into liver cells for metabolism and clearance. Variations in SLCO1B1 can alter transporter activity—leading to changes in simvastatin blood levels and the risk of muscle-related side effects such as myopathy.

SLCO1B1 genetic variants fall into functional categories—from increased to poor transporter activity—which influence how much simvastatin enters the liver. Reduced transporter activity leads to higher circulating levels of the drug, raising the likelihood of muscle toxicity, while increased activity generally results in normal drug handling and typical risk profiles.

Increased Function

• Effect on drug levels: Normal simvastatin exposure
• Clinical consequence: Typical risk of muscle-related side effects
• Side effects: Low risk of myopathy, generally mild when they occur

Normal Function

• Effect on drug levels: Normal simvastatin exposure
• Clinical consequence: Typical risk of muscle-related side effects
• Side effects: Low risk of myopathy, generally mild when they occur

Decreased Function

• Effect on drug levels: Increased simvastatin exposure
• Clinical consequence: Elevated risk of muscle-related side effects
• Side effects: Moderate risk of myopathy, muscle pain occurs occasionally

Possible Decreased Function

• Effect on drug levels: Increased simvastatin exposure
• Clinical consequence: Elevated risk of muscle-related side effects
• Side effects: Moderate risk of myopathy, muscle pain occurs occasionally

Poor Function

• Effect on drug levels: Markedly increased simvastatin exposure
• Clinical consequence: High risk of muscle-related side effects
• Side effects: Severe myopathy possible, although rare

Possible Poor Function

• Effect on drug levels: Markedly increased simvastatin exposure
• Clinical consequence: High risk of muscle-related side effects
• Side effects: Severe myopathy possible, although rare

Indeterminate

• Effect on drug levels: Unknown
• Clinical consequence: No specific guidance; follow standard dosing
• Side effects: Unknown

Not available

• Effect on drug levels: Unknown
• Clinical consequence: No specific guidance; follow standard dosing
• Side effects: Unknown

SLCO1B1 Dosing Guideline

Phenotype	Clinical Consequence	Guideline Recommendation
Increased Function	Typical myopathy risk and normal statin exposure	Prescribe desired starting dose and adjust based on disease-specific guidelines.
Normal Function	Typical myopathy risk and normal statin exposure	Prescribe desired starting dose and adjust based on disease-specific guidelines.
Decreased Function	Increased simvastatin exposure and higher risk of muscle side effects	Consider alternative statin (e.g., atorvastatin, pravastatin, rosuvastatin) or limit simvastatin to <20 mg/day.
Possible Decreased Function	Increased simvastatin exposure and higher risk of muscle side effects	Consider alternative statin (e.g., atorvastatin, pravastatin, rosuvastatin) or limit simvastatin to <20 mg/day.
Poor Function	Markedly increased simvastatin exposure and high risk of muscle side effects	Use alternative statin based on potency; if simvastatin is used, limit dose to <20 mg/day.
Possible Poor Function	Markedly increased simvastatin exposure and high risk of muscle side effects	Use alternative statin based on potency; if simvastatin is used, limit dose to <20 mg/day.
Indeterminate	No CPIC guidance available	Initiate therapy with recommended starting dose.
Not available	No CPIC guidance available	Initiate therapy with recommended starting dose.

Examples from guidelines include alternative statins such as atorvastatin, pitavastatin, pravastatin, rosuvastatin, fluvastatin, and lovastatin. Selection and dosing should be guided by clinical factors and disease-specific recommendations.

• CPIC – Guideline for Simvastatin and SLCO1B1
• FDA – Table of Pharmacogenetic Associations