Statin-induced myopathy risk

SLCO1B1 ferries statin drugs into the liver. A reduced-function variant lets statins build up in the blood, raising the chance of muscle pain, most relevant for simvastatin.

What this SLCO1B1 variant does

SLCO1B1 makes OATP1B1, the transporter that pulls statins out of the bloodstream and into liver cells, which is both where they do their work and how they leave the body. This variant reduces that uptake, so more of the drug stays in circulation and reaches muscle.

Statin muscle symptoms are common and mostly not genetic, but the subset driven by high systemic exposure is exactly what this variant predicts.

How strong the evidence is

This is one of the best-supported pharmacogenetic associations in medicine. In the SEARCH trial analysis of people taking simvastatin 80 mg, carrying one copy of the reduced-function allele carried 4.5 times the odds of myopathy and carrying two carried 17 times, compared with people with neither.

CPIC, the international body that writes prescribing guidance for genetics, rates the evidence level A and issued an updated statins guideline in 2022 that replaces its earlier simvastatin-specific ones. ClinVar records the variant as a drug-response variant with three-star review status.

It matters most for simvastatin

The effect is not uniform across the statin class. It is strongest for simvastatin, which is why the original guideline was written around that drug, meaningful for atorvastatin and pitavastatin, and smaller for others such as fluvastatin. Rosuvastatin exposure is also affected, though the muscle association is weaker.

The practical translation used in guidelines is to avoid high-dose simvastatin in carriers and either lower the dose or use a different statin. That is a prescribing decision, and the point of knowing is to raise it if statin muscle symptoms ever appear, not to change a prescription yourself.

How common it is

In 1000 Genomes reference data, about 26% of European-ancestry individuals carry one reduced-function copy and 2% carry two, with similar figures in East Asian samples, lower in South Asian at around 9%, and lowest in African-ancestry samples at around 6%.

So roughly a quarter to a third of people of European or East Asian ancestry carry at least one copy. This is common variation that shifts a dose decision, not a rare defect.

What this variant does not tell you

Most statin muscle complaints are not caused by this variant, and blinded trials have repeatedly found that many symptoms attributed to statins recur on placebo. A normal result here does not mean symptoms are imagined, and a variant result does not prove a given ache is drug-related.

Serious muscle injury, meaning rhabdomyolysis, is rare and has other causes including drug interactions, particularly with some antibiotics, antifungals and fibrates. Unexplained severe muscle pain with dark urine while taking a statin is an urgent clinical matter regardless of genotype.

What each rs4149056 genotype means

rs4149056 has three possible genotypes: TT, CT and CC.

Normal statin response (rs4149056 TT). You have the normal-function version of SLCO1B1, the transporter that moves statin drugs into your liver. Statins are cleared as expected, so your risk of statin-related muscle problems from this gene is typical.

Higher statin muscle-pain risk (rs4149056 CT). You carry one copy of a variant that slows how your liver takes in statin medications, especially simvastatin. The drug can build up to higher levels in your blood, which raises the chance of muscle aches if you take it. If you're ever prescribed a statin, it's worth mentioning to your doctor, who might choose a lower dose or a different one.

High statin muscle-pain risk (rs4149056 CC). You have two copies of the reduced-function SLCO1B1 variant, so statins (especially simvastatin) clear slowly and can build up, raising the risk of muscle pain or weakness. If you ever need a statin, this is important to share with your doctor, who can usually pick a statin and dose that suit you.

Evidence & sources

Across global populations, about 2% of people carry two copies of this variant, and about 74% carry none.

CPIC provides dosing guidance for simvastatin based on this gene.

This variant appears in 65 published genetic studies: PubMed 18650507 · PubMed 19414484 · PubMed 22829776 · PubMed 23093944 · PubMed 23823483 · PubMed 24816252 · PubMed 27073872 · PubMed 28429243 · PubMed 29507422 · PubMed 30275531 · PubMed 30367059 · PubMed 30595370 · PubMed 31220337 · PubMed 31578528 · PubMed 31628463 · PubMed 31959995 · PubMed 32042192 · PubMed 32047095 · PubMed 32154731 · PubMed 32888493 · PubMed 32888494 · PubMed 32961594 · PubMed 33031748 · PubMed 33177712 · PubMed 34321204 · PubMed 34337532 · PubMed 34503513 · PubMed 34563731 · PubMed 34594039 · PubMed 34887591 · PubMed 35050183 · PubMed 35078996 · PubMed 35192695 · PubMed 35213538 · PubMed 35347128 · PubMed 35652242 · PubMed 35668104 · PubMed 35942816 · PubMed 36224396 · PubMed 36357675 · PubMed 36635386 · PubMed 36653534 · PubMed 36764567 · PubMed 37253714 · PubMed 37277652 · PubMed 37524825 · PubMed 37963177 · PubMed 38116116 · PubMed 38448586 · PubMed 38493369 · PubMed 38658550 · PubMed 38711861 · PubMed 39024449 · PubMed 39091897 · PubMed 39406924 · PubMed 39414775 · PubMed 39644095 · PubMed 39789286 · PubMed 39927731 · PubMed 40229599 · PubMed 40316537 · PubMed 40360795 · PubMed 40436827 · PubMed 40545721 · PubMed 41044249.

Common questions

Should I stop my statin because of this result? No. The evidence supports adjusting which statin or what dose, not stopping treatment, and the cardiovascular benefit of statins in people who need them is large. This is a result to mention to your prescriber, particularly if you take simvastatin at a high dose or have muscle symptoms.

Does this affect all statins? Not equally. The association is strongest for simvastatin, moderate for atorvastatin and pitavastatin, and weaker for others. That is why guidelines suggest switching statin rather than abandoning the class.

Related

Abacavir hypersensitivity (HLA-B*57:01) · CYP2C19 metabolizer status (clopidogrel & others) · Fluoropyrimidine (5-FU) toxicity risk · Gilbert syndrome (UGT1A1 gene) · Opioid receptor response (OPRM1 A118G) · Thiopurine metabolism (TPMT and NUDT15 genes) · Warfarin dose sensitivity