SLCO1B1 Genotyping for Statins (Point-Counterpoint)

Abstract

There is a great deal of interest in understanding genes that predict drug response. In January, South Dakota Medicine began publishing a series of monthly articles dedicated to reviewing the pros and cons of gene-based drug dosing.¹ The first article in this series was a point-counterpoint argument by local content experts exploring the utility of CYP2C19 (cytochrome P450 gene, subfamily 2C19) genotyping for patients taking clopidogrel.² The second article explored genotype-guided warfarin therapy. We now present the third article in this series, a discussion of the genes that impact patient risk for myopathy on statins.

Russell A. Wilke, MD, PhD, FACP: “The SLCO1B1 Gene Impacts Risk for Statin Myopathy”

HMG Co-A reductase inhibitors (statins) are among the most commonly prescribed drugs in the industrialized world. Currently there are half a dozen drugs available for clinical use within this class, and they vary in clinical efficacy. While they are also generally regarded as safe, greater than 1 percent of patients exposed to statins develop myalgias.³ Fortunately, only 0.1 percent of exposed patients have a serum creatine phosphokinase (CPK) level exceeding 3xULN (upper limit of normal) accompanied by muscle pain sufficient to justify stopping the medication. This phenomenon, the development of clinically relevant statin myopathy, is dose-dependent. In fact, the SEARCH Trial (“Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine” Trial) demonstrated that myopathy occurs at a higher frequency (approaching 1 percent) in patients using 80 mg simvastatin daily.⁴ The Food and Drug Administration (FDA) therefore issued a warning in 2011, discouraging the use of high-dose simvastatin.

Early studies assessed the impact of several well-characterized candidate genes (e.g., the HMG-CoA reductase gene itself, and multiple CYP genes encoding the cytochrome P450 enzymes) on statin myopathy risk. Although some of these studies revealed statistically meaningful association with statin muscle toxicity,^5–7 the effect size was small and none of these drug-gene relationships was found to be clinically actionable. Then, in 2008, the SEARCH Trial investigators conducted a genome-wide association study revealing that variation in a hepatic uptake transporter gene, SLCO1B1 (solute carrier gene, subfamily 1B1), was a strong predictor of myopathy in patients taking simvastatin (20-fold increase in myopathy risk).

Because the strength of association between SLCO1B1 genotype and statin myopathy varies drug-by-drug,⁸ this information may be clinically actionable. In 2012, we published a gene-based dosing guideline for statins,⁹ and in 2015 we published the automated decision support for this relationship in one of the largest commercial electronic medical records in the U.S.¹⁰ In patients with an abnormal SLCO1B1 gene, EPIC can now display kinetic data for various statins, allowing clinicians to balance risk for myopathy against lipid-lowering efficacy when selecting a drug within this class.¹⁰

As the field of medical informatics changes the landscape upon which we practice, it seems inevitable that genomic data will increasingly be available through wide-scale expansion of electronic medical records. Because statins are the most commonly prescribed drugs in the U.S., and because SLCO1B1 gene variants cause a striking elevation in risk for myopathy, gene-based statin dosing will soon be a clinical reality.

Joseph Fanciullo, MD, FACR: “Gene-based Statin Dosing is not Ready for Prime Time”

The FDA currently requires genetic or genomic information in the labels of nearly 200 prescription medications. In some cases, genotyping is mandatory. For most, however, genotyping is optional. Statins are among the latter group. There are at least two reasons why gene-based drug dosing for statins remains optional: 1) some cases of statin muscle toxicity are idiosyncratic, due to autoimmune myositis rather than myopathy, and 2) risk prediction models need to be measured against equally accurate models of statin efficacy.

Most human traits are influenced by multiple genetic factors of relatively small effect, and the search for genetic markers of statin efficacy is therefore still in its infancy. Half a decade ago, an international genome wide meta-analysis identified nearly 100 genetic factors contributing to low-density lipoprotein (LDL) cholesterol level.¹¹ The genetic architecture underlying statin-induced change in LDL cholesterol level is also polygenic. Using a similar design (genome wide meta-analysis), we and others recently published a list of genes impacting the lipid lowering efficacy of statins.¹² In addition to validating previously known determinants of pretreatment LDL cholesterol level, this study identified at least two novel loci influencing the cholesterol response to statins: SORT1 (sortilin gene, subfamily 1) and SLCO1B1. So genetic variants in SLCO1B1 not only impact myopathy risk, they impact the efficacy of statins. The contributions made by other genes like SORT1 remain poorly understood.¹³

For most clinicians, gene-based dosing guidelines are only desirable when they pertain to preventable events (e.g., muscle-related side effects leading to interruption of statin therapy, or potentially fatal cases of rhabdomyolysis). While myalgias and myopathy appear to present along a clinical continuum, it is unclear if the SCLO1B1 gene variants predict the entire spectrum of statin myopathy. The SEARCH trial defined statin-related myopathy based on clinical symptoms and a threshold elevation in CPK.⁴ However, some patients may develop muscle pain and stop their statin therapy irrespective of CPK levels. Furthermore, some of the more clinically severe cases of statin induced muscle damage have been due to a different pathophysiological process, the development of autoimmune myositis. This process appears to be distinct from typical statin myopathy. It is characterized by the presence of anti-HMGCR (hydroxymethylglutaryl-coenzyme-A reductase) autoantibodies, and persistent muscle injury not reversed after cessation of statins. Patients with autoimmune myositis often require immunosuppressive therapy. When patients with this syndrome were studied, there did not appear to be an association with the SCLO1B1 gene polymorphism.^14,15 Therefore, genetic determinants of myopathy may not predict necrotizing myositis,¹⁶ and more research is needed to clarify the immunogenetic contribution to this adverse drug reaction^17,18 before we are ready to begin using genetics for statin dosing.

Additional layers of complexity include cost and insurance coverage. At present, SLCO1B1 genotyping costs approximately $400, and most third party payers are unwilling to reimburse patients for this test. As the field of pharmacogenetics moves forward, insurance providers appear more willing to cover the cost of gene variants associated with outcome for drugs with a narrow therapeutic index (e.g., anticoagulants or antineoplastics). Because statins have a wide therapeutic index, most clinicians simply “start low and go slow” – titrating dose upward while monitoring for adverse effects.

For drugs with a wider therapeutic index, like statins, more information is needed before we proceed. Risk prediction models will need to incorporate information from multiple genes impacting mechanism and metabolism, as well as immune response. Perhaps in the future, these models may be able to predict rare cases of autoimmune myositis in addition to mild myopathy. Until we get there, however, this approach is not ready for prime time.