7.07.2 Statins
Statins are widely used in the United States, with one in four Americans aged 40 and older taking a statin. Atorvastatin and simvastatin are the most prescribed. Statins have a wide therapeutic index. The most common adverse drug reaction is skeletal muscle toxicity, which manifests as statin-associated muscle symptoms (SAMS). SAMS can range from myalgia (pain without evidence of muscle degradation) to myopathy (evidence of muscle degradation with or without myalgia) to rhabdomyolysis (severe muscle damage with the risk of acute kidney injury). Most cases of SAMS are likely due to direct statin myotoxicity, which is concentration-dependent. SAMS are more frequent in clinical practice than in blinded, placebo-controlled trials, and data from the National Health and Nutrition Examination Survey suggest that the “number needed to harm” may be as high as 17. SAMS frequently lead to statin discontinuation, which can result in higher cholesterol levels and increased risk of cardiovascular disease if statins are not reinitiated.
SLCO1B1 is the protein product of the SLCO1B1 gene. It is a member of the solute carrier organic anion transporter family. This protein is also known as OATP1B1 or OATP-C. SLCO1B1 facilitates the hepatic uptake of statins, as well as other exogenous and endogenous compounds such as bilirubin and 17-beta-glucuronosyl estradiol (Niemi et al., 2011).
When SLCO1B1 function is decreased due to genetic variability or drug-mediated inhibition, it can lead to a marked increase in cellular exposure to statins, the putative causal factor underlying the link to statin-associated muscle symptoms (SAMS) (Turner and Pirmohamed, 2019). CPIC guidelines, which reflect the American College of Cardiology statin intensity recommendations, should be consulted as these recommendations are complex. In general, however, those persons with predicted SLCO1B1 decreased function should avoid high-intensity, high dose statin regimens and be aware of potential risk of SAMS in moderate-intensity and high dose regimens. Those with SLCO1B1 poor function should avoid high to moderate doses of most statins.
Genetic variations in CYP2C9 have been associated with increased exposure to fluvastatin. However, the pharmacokinetics or pharmacodynamics of other statins are not affected by CYP2C9 genetic variations. For individuals who are intermediate metabolizers, it is recommended that they avoid fluvastatin doses greater than 40 mg. Similarly, for poor metabolizers, it is recommended avoiding fluvastatin doses greater than 20 mg. If higher doses of fluvastatin are required to achieve the desired efficacy, an alternative statin should be considered.
ABCG2 encodes the ATP-binding cassette G2 transporter. This transporter is expressed in various tissues, including the liver, blood-brain barrier, and intestine. It facilitates the export of compounds out of cells into the extracellular space. The recommendations for ABCG2 are specific to rosuvastatin. Individuals with ABCG2 poor function are advised to start with a rosuvastatin dose of ≤20 mg. However, if a higher dose is needed to achieve the desired efficacy, an alternative statin or combination therapy (e.g., statin + other class agent) can be used. Individuals with ABCG2 decreased function may have an increased risk of developing adverse effects, such as SAMS, when taking higher doses of rosuvastatin.
The recommendations given above are primarily applicable to patients who are either receiving a new or a revised (dose or type) statin prescription. However, for patients on a stable statin and dose for at least 4 weeks without any symptoms suggestive of SAMS, it is reasonable to continue that statin and dose long-term, if their SLCO1B1 genotype-statin dose combinations fall within the moderate SAMS risk categories. In contrast, if those patients have been receiving statin therapy for less than 4 weeks, then clinicians may consider changing to a lower SAMS risk statin/dose to prevent the development of SAMS.
For patients who fall into the high SAMS risk categories, and they have been taking that statin therapy for at least 1 year without any negative effects, then it is considered safe to continue that statin therapy long-term. If those patients have been taking statin therapy for less than 1 year, then clinicians may consider changing to a lower SAMS risk statin/dose to reduce the risk for development of SAMS. These recommendations for the minimum duration of statin therapy for continued safe use long-term are primarily based on expert opinion and the onset of SAMS observed for simvastatin in different SLCO1B1 genotypes in a single prospective clinical trial.
The prevalence of statin use is high, and preemptive testing for SLCO1B1, ABCG2, and CYP2C9 may provide several potential benefits. One of these benefits is the reduction in the incidence of SAMS by identifying individuals who are at a significant risk of developing SAMS and recommending a lower statin dose or an alternative statin with a lower SAMS risk. Although there is a lack of prospective data showing that prescribing based on genetic testing results can alter SAMS incidence, emerging data indicate that applying SLCO1B1 testing to clinical practice can result in improvements in patients’ perceptions of statins, appropriate statin prescribing, and neutral data on patient-reported adherence. However, there is mixed data on the reduction of LDL-cholesterol levels as another potential benefit.
These recommendations are based on clinical trials with limited evidence for their impact in broad, population-based implementation. Further research will assist in optimizing statins across all people.