Does the SLCO1B1 rs4149056 CT genotype reduce hepatic statin transport and raise muscle-symptom risk?

The rs4149056 CT genotype in SLCO1B1 is a clinically relevant intermediate reduced-function state for the hepatic statin transporter OATP1B1. The claim is supported, particularly for simvastatin and, to a lesser extent, atorvastatin.

Transport and pharmacokinetics

• The C allele encodes p.Val174Ala, associated with reduced functional OATP1B1 expression/localization at the hepatocyte basolateral membrane. This reduces hepatic uptake and increases circulating drug concentrations.
• CT carriers generally have exposure intermediate between TT and CC genotypes. For simvastatin acid, each C allele has been associated with roughly 57–61% higher AUC, consistent with approximately 1.6-fold CT-versus-TT exposure on average.
• Evidence is strongest for simvastatin acid and atorvastatin. Exposure effects with pravastatin, rosuvastatin, and pitavastatin are smaller or more variable; rosuvastatin estimates may also be influenced by ancestry and ABCG2 variation.

Muscle-toxicity implications

• Higher systemic statin exposure provides a coherent concentration-dependent mechanism for muscle toxicity, especially CK-defined myopathy with simvastatin.
• In the 80-mg simvastatin SEARCH cohort, five-year myopathy risk was approximately 3% in CT versus 0.6% in TT carriers; CC carriers had substantially higher risk (18%). Broader data found CT-associated myopathy/rhabdomyolysis odds of 1.4 (95% CI 1.02–1.92) versus TT.
• This association is better established for objective myopathy than for nonspecific muscle pain, weakness, or fatigue.

Clinical implications

• Risk is not uniform across statins or doses. High-dose simvastatin is the clearest concern; CPIC guidance supports avoiding simvastatin 80 mg in CT carriers and considering a lower dose or alternative statin.
• Interacting drugs, dose, exercise, endocrine disorders, and comorbidities remain important determinants of muscle symptoms.

Bottom line

• SLCO1B1 rs4149056 CT plausibly and measurably reduces hepatic statin transport, can raise exposure—most convincingly for simvastatin—and modestly increases susceptibility to dose-dependent statin myopathy.