Genetic Testing for Statin-Induced Myopathy
|Subsection||Last Review Status/Date
Reviewed with Literature search/5:2014
|Original Policy Date
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Statin drugs, which are widely used, can cause muscle-related side effects. Serious myopathy, i.e., myositis or rhabdomyolysis, can also occur and may be associated with genetic factors such as variants in the SLCO1B1 gene. Commercially available tests for the presence of SLCO1B1 variants are currently marketed for use in predicting the risk of myopathy for patients taking statins.
Statin drugs are the primary pharmacologic treatment for hypercholesterolemia throughout the world. In the United States, there are an estimated 38 million individuals taking statins as of 2008. (1) Use of statins is associated with an approximately 30% reduction in cardiovascular events across a wide variety of populations. (2)
Statins are associated with a known risk of muscle-related symptoms, and these are the most common side-effects of statin drugs. Myopathy is a general term for muscle toxicity. The following three categories of statin-induced myopathy have been recommended by an ACC/AHA/NHLBI advisory committee (3):
- Statin-induced myalgia, defined as any muscle symptoms that occur without an elevation of serum creatinine kinase (CK);
- Statin-induced myositis, defined as muscle symptoms with an elevation of serum CK; and
- Statin-induced rhabdomyolysis, defined as markedly severe muscle symptoms with an elevation of CK greater than 10 times normal with an elevation in serum creatinine.
Statin-induced myalgia is the most common manifestation of myopathy and is characterized by muscle pain, cramps, fatigue, and/or weakness. (4) Myalgias without other clinical manifestations are not associated with clinically important adverse events and resolve when the statin is discontinued.
The incidence of myalgia varies widely in the published literature. In clinical trials, these symptoms have been reported in 1.5-3.0% of patients, and in most trials, the rate of myalgias in patients on statin therapy is not increased compared to placebo treatment. (5) In observational studies, higher rates of 10-15% have been reported. (2)
Myositis is much less common that myalgias, with an estimated rate of 5 per 100,000 patient-years, and an estimated per-person incidence of 0.01%. (5) In virtually all cases, myositis resolves with discontinuation of the statin. Rhabdomyolysis is the most severe clinical manifestation of statin-induced myopathy and can be life-threatening. The National Lipid Association Statin Safety Assessment Task Force estimated that rhabdomyolysis occurs at a rate of 1.6 per 100,000 patient years, and the U.S. Food and Drug Administration (FDA) adverse events reporting system has estimated a rate of 0.7 per 100,000 patient-years. (5) A systematic review published in 2006 combined results from 20 clinical trials, and estimated the rate of rhabdomyolysis to be 1.6 cases per 100,000 patient-years. (6) Fatalities from statin-induced rhabdomyolysis can occur, but the mortality rate is not well-defined. The FDA estimated that deaths for rhabdomyolysis occur at a rate of less than 1 death per million prescriptions. (3)
There are a number of clinical factors that are associated with an increased risk of statin myopathy. Statin dose is probably the strongest risk factor, with an estimated 6-fold increase for patients on high-dose statins. (7) Age is also a strong risk factor. One study reported that patients older than 65 years of age required hospitalization for statin-induced myositis at a rate that was 4 times higher than for younger patients.(8) Some statins may be associated with higher risk than others, and concomitant administration of certain drugs such as gemfibrozil and amiodarone is associated with higher rates of statin myopathy in clinical trials. (7) Other factors that may be associated with myopathy include female gender and intense physical exercise. (7)
The perceived risk of statin-induced myopathy may be a contributing reason for suboptimal statin use in patients with indications. Less than 50% of patients in the U.S. who would benefit from statins are currently taking them, and a substantial part of this is the result of non-adherence to prescribed statins. (1)
Genetic factors associated with statin-induced myopathy
There are a variety of genetic factors associated with statin myopathy. The cytochrome p450 system in the liver is the main pathway by which statins are metabolized. Numerous genetic variants in cytochrome p450 proteins affect the pharmacokinetics of statin metabolism and serum statin levels. (2) Other genetic variants that affect statin metabolism, efficacy, and susceptibility to adverse effects involve variations in the apolipoproteins such as apo E, variations in the cholesterol ester transfer proteins (CETP), or variations in the coenzyme Q pathway. (1)
Variations in the SLCO1B1 gene also affect statin metabolism and are among the most well-studied genetic variants. These are also the genetic markers for which there are commercially available tests. This gene codes for a transporter protein that is part of the solute carrier organic ion transporter (SLCO) system, which mediates the influx and metabolism of statins in the liver. (2) Single nucleotide polymorphisms (SNPs) in this gene are associated with variations in the risk of statin-induced myopathy. The T/T allele is the wild-type and associated with the lowest risk of myopathy. The C/C allele is associated with a higher risk of myopathy, and the T/C allele with an intermediate risk. The T allele has a prevalence of approximately 0.87, and the C allele has a prevalence of approximately 0.13. (4)
While SLCO1B1 variants have been the most studied in statin metabolism, other genes have also been studied, including ABCB1, which encodes ATP-binding cassette (ABC) transporters subfamily B member 1 (ABCB1/P-glycoprotein 1), ABCG2, which encodes ABC transporters subfamily G member 2 (ABCG2/breast cancer resistance protein), and the coenzyme Q2 (COQ2) homolog gene.
Several commercial labs offer genetic testing for SLCO1B1 variants. Boston Heart Diagnostics™ markets a test for the statin-induced myopathy (SLCO1B1) genotype. This test uses real-time polymerase chain reaction (PCR) to identify patients with the T/T, T/C, or C/C genotype. Available online at: http://www.bostonheartdiagnostics.com/science_portfolio_statin.php.
Berkeley Heart Lab™ offers a similar genetic test for SLCO1B1 variants. Details of how this test is performed are not provided on the company website. Available online at: http://www.bhlinc.com/clinicians/test-descriptions/SLCO1B1-Genotype-Test
Arup Laboratories markets a test for SLCO1B1 genetic variants that uses real-time PCR with high resolution melting analysis to identify the rs4149056C variant in the SLCO1B1 gene. Available online at: http://ltd.aruplab.com/tests/pub/2008426
The commercially available tests for SLCO1B1 are laboratory developed tests and not subject to FDA approval.
Genetic testing for the presence of variants in the SLCO1B1 gene for the purpose of identifying patients at risk of statin-induced myopathy is considered not medically necessary.
There is no specific CPT code for genetic testing for SLCO1B1.
Effective July 1, 2013, code 81400 Molecular pathology procedure, Level 1 (eg, identification of single germline variant [eg, SNP] by techniques such as restriction enzyme digestion or melt curve analysis) – will include testing for SLCO1B1 (solute carrier organic anion transporter family, member 1B1) (eg, adverse drug reaction), V174A variant.
Prior to July 1, 2013 and for testing of variants other than V174A, the unlisted molecular pathology procedure code 81479 would be reported.
BlueCard/National Account Issues
No applicable information.
This policy was created in June 2013 and updated periodically with literature review. The most recent update with literature review covered the period through April 1, 2014. Published articles were selected that reported on the analytic validity, clinical validity, and clinical utility of genetic testing for statin-induced myopathy.
Two labs (Boston Heart Diagnostics™ and Arup Laboratories) perform the test by real-time polymerase chain reaction (PCR). This technique allows detection and amplification of DNA fragments to be performed simultaneously. While this is an accepted method for genetic analysis and generally has high accuracy, no published information was found on the accuracy of this technique for detecting genetic variants associated with statin-induced myopathy. Arup Laboratories reports that the test’s analytic sensitivity and specificity are greater than 99% for identification of the presence of 1 or 2 copies of SLCO1B1*5.(9)
There are no studies that report the sensitivity or specificity of genetic testing for statin-induced myopathy. Studies were identified that report the degree of risk for myopathy associated with the SLCO1B1 genetic variants. These include genome-wide association (GWA) studies, case-control studies, cohort analyses,
and clinical trials. Representative types of each study are included next.
GWA studies have reported that SLCO1B1 variants are associated with statin-induced myopathy. The SEARCH study group published a GWA study in 2008 based on data from the SEARCH trial.(4) This was a randomized controlled trial (RCT) of 12,064 patients with a prior myocardial infarction (MI) randomized to 80 mg simvastatin or 20 mg simvastatin. Of the 6031 patients in the 80-mg-statin group, 48 (0.8%) had an elevation of serum CK level more than 10 times normal, and an additional 48 patients (0.8%) had a creatinine kinase (CK) level that was more than 3 times normal and more than 5 times the baseline level. These subjects were matched with 96 control subjects without CK elevations, matched for gender, age, renal function, and ancillary medication use. Adequate DNA was available for 85 patients with myopathy
and 90 controls, and these patients formed the study group for derivation of the genome associations.
The SLCO1B1 locus was the single nucleotide polymorphism (SNP) that had a strong association with myopathy, at a corrected p value of 0.001. The estimated odds ratio (OR) for myopathy in patients with a single C allele was 4.3 (95% confidence interval [CI], 2.5 to 7.2), and the estimated OR for patients homozygous for the C allele was 17.4 (95% CI, 4.8 to 62.9). Based on these data, the cumulative risk of developing myopathy after 6 years of treatment with 80-mg simvastatin was 0.6% for patients with the T/T allele, 3% for patients with the T/C allele, and 18% for patients with the C/C allele. Other clinical factors that predicted a risk of myopathy were female gender (relative risk [RR], 1.8; 95% CI, 1.1 to 2.8), age 65 and older (RR=2.2; 95% CI, 1.4 to 3.4), impaired renal function (RR=2.2; 95% CI, 1.4 to 3.4), use of amiodarone (RR=6.4; 95% CI, 3.4 to 12.1), use of calcium antagonists (RR=1.7; 95% CI, 1.2 to 2.6), and diabetes mellitus (RR=1.7; 95% CI, 1.0 to 2.9).
The SEARCH investigators replicated the association of the SLCO1B1 with myopathy in 16,664 patients from a separate RCT, the Heart Protection Study. In this study, all patients were treated with 40 mg of simvastatin, and 23 (0.1%) were identified with CK levels greater than 10 times normal. SLCO1B1 variants were also strongly associated with myopathy in this replication study, with a corrected p value of 0.004). The estimated OR for the presence of 1 C allele was 2.6 (95% CI, 1.3 to 5.0).
The STRENGTH (Statin Response Examined by Genetic Haplotype Markers) study was a randomized trial that examined statin response and safety by dose of statin, type of statin, and by presence of genetic markers.(10) A total of 509 patients were randomized to various doses of atorvastatin, pravastatin or simvastatin and followed for the presence of adverse events, including myopathy. The presence of at least 1 variant on the SLCO1B1 gene was associated with an increased rate of adverse events (37% vs 25%, p=0.03). There was also evidence for a “dose-response” effect, with the risk of adverse events being 19% with no variant alleles, 27% with 1 variant allele, and 50% with 2 variant alleles (p=0.01 for trend). The association between SLCO1B1 gene status and adverse event rates did not appear to be present for patients who received pravastatin.
A case-control study reporting on the risk of myopathy associated with SLCO1B1 variants was reported in 2012.(11) This study identified cases with statin-induced myopathy, defined as muscle symptoms with a CK elevation at least 10 times normal, from 2 large lipid clinics in the Netherlands. Twenty-five cases of myopathy were identified from 9000 total patients, for a prevalence of 0.26%. These patients were matched for age, gender, statin type, and statin dose, with 84 patients who did not have myopathy. In the whole cohort of patients taking any statin, there was a nonsignificant trend toward an increase in myopathy for patients with a SLCO1B1 variant (OR=1.5; 95% CI, 0.58 to 3.69; p=0.21). When restricted to patients on simvastatin, the association was stronger but did not quite reach statistical significance (OR=3.2; 95% CI, 0.83 to 11.96; p=0.06).
Carr et al reported results from a similar case-control study evaluating the risk of statin-induced myopathy associated with SLCO1B1 variants.(12) The authors identified 77 statin-induced myopathy patients (serum CK greater than 4 times the upper limit of normal) and 372 statin-tolerant controls from a large database of anonymous longitudinal medical records in the UK. In multiple logistic regression analyses to determine statin-associated myopathy risk, the presence of the C allele in the SLCO1B1 gene was significantly associated with myopathy: for all myopathy, the adjusted OR per C-allele was 2.08 (95% CI, 1.3 to 3.32); for severe myopathy, the adjusted OR per C-allele was 4.47 (95% CI, 1.84 to 10.84). When the analysis was restricted to only those patients receiving simvastatin (n=281), there was a significant association between the SLCO1B1 gene status and myopathy (adjusted OR per C-allele=2.13; 95% CI, 1.29 to 3.54; p=0.014). In contrast, when the analysis was restricted to only those patients receiving atorvastatin (n=121), no significant association was found. Variations in the COQ2 gene were not associated with statin-induced myopathy.
Some evidence, including the Carr et al results, suggest that the association between myopathy and SLCO1B1 genotype is most pronounced for simvastatin. Danik et al evaluated the role of SLCO1B1 polymorphisms as effect modifiers for clinical myalgia in the Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which randomly allocated subjects to rosuvastatin (20 mg/day) or placebo.(13) Among the 4404 subjects allocated to rosuvastatin, there was no significant association
between SLCO1B1 gene status and either muscle symptoms or a diagnosis of rhabdomyolysis, myopathy, or myositis.
In a subanalysis of a prospective population-based cohort study of chronic diseases in the elderly population, deKeyser et al evaluated whether SLCO1B1 polymorphisms modified the risk of adverse drug reactions during statin therapy among 2080 patients who received simvastatin or atorvastatin and had SLCO1B1 genotype available.(14) The study’s primary outcome was reduction in statin dose or switch to another statin-lowering drug as an indicator for an adverse drug reaction. Among simvastatin users, the T→C polymorphism was significantly associated with the primary outcome. Patients who had the CC genotype had a hazard ratio for dose decrease or switch of 1.74 (95% CI, 1.05 to 2.88). A similar association was not seen among atorvastatin users.
Ferrari et al conducted a case-control study among patients treated with atorvastatin, rosuvastatin, or simvastatin to assess the contribution of polymorphisms in the SLCO1B1, ABCB1, and ABCG2 genes to the risk of statin-induced myopathy.(15) Cases (n=33) included patients with statin-induced elevations in serum CK of greater than 3 times the upper limit of normal and were compared to 33 matched controls. Patients with increased CK levels had significantly increased odds for the SLCO1B1 C allele or the ABCB1 T allele: OR of 8.86 (p<0.01) and 4.67 (p<0.05), respectively. Patients with increased CK levels did not have a significantly increased odds of having the ABCG2 genotype.
There were no studies identified that reported direct evidence on the clinical utility of genetic testing for statin myopathy. Direct evidence for clinical utility in this setting would come from studies that demonstrate that using SLCO1B1 genotype to inform statin therapy (statin dose or choice of specific drug) has positive outcomes in terms of lower rates of myopathy with adequate lipid control and tolerability of alternative treatments. Indirect evidence includes the predicted number of patients who avoid statin myopathy as a result of genetic testing. This number is uncertain because there are a number of actions that can be taken as a result of genetic testing. Statins can be stopped or not started, a lower dose can be used, and other risk factors can be avoided, such as use of amiodarone. Despite the uncertainty in the precise number of events avoided, the number will necessarily be low because of the low underlying rate of serious events.
Several institutions have implemented electronic medical record-based clinical decision support systems to guide statin dosing and follow-up for patients started on a statin based on patients’ SLCO1B1 status, including Vanderbilt University Medical Center(7) and St. Jude Children’s Research Hospital.(16) However, studies that demonstrate that such systems are associated with improved clinical outcomes are lacking.
When statin use is reduced or eliminated, the reduction in statin myopathy needs to be weighed against the increased cardiovascular events that may occur as a result of this change. In patients with a moderate to high risk of cardiovascular events, the probability of MI over a 10-year period may be in the range of 10% to 20%. This event rate is substantially higher than the probability of serious myositis and rhabdomyolysis. As a result, if statin drugs are avoided because of genetic testing, the number of MIs that will result may exceed the number of myopathy episodes avoided, and net harm may result. Because there are no alternative agents that can reduce the rate of cardiovascular events to the extent as dostatins, it may not be possible to ameliorate this net harm by a change to an alternate lipid-lowering strategy.
Ongoing Clinical Trials
A search of the database ClinicalTrials.gov on April 1, 2014, using the term “SLCO1B1” identified 1 comparative study evaluating the utility of genetic testing in preventing statin-induced myopathy:
- Genetically Guided Statin Therapy (NCT01894230). This study randomizes patients with statin nonuse due to either (a) Prior side effects thought to be attributed by the patient to statin use AND/OR (b) Physician removal of statin due to presumed associated side effects to either usual care to an intervention that will include report of SLCO1B1*5 genotype to patient and provider at the study outset. The primary study outcome is change in medication adherence. Enrollment is planned for 375 subjects; the planned study completion date is January 2016.
Statin muscle symptoms are the most common adverse effect of statins, and serious myopathy or rhabdomyolysis occurs in a very small number of patients treated with statins. An association between genetic variants of the SLCO1B1 gene and statin myopathy has been reported. This association has been found in genome-wide association studies that indicate a several-fold risk of statin myopathy associated with genetic variants. Evidence from case-control studies and clinical trials also show a possible association, but the quantity of evidence is small and the association has not been demonstrated to be strong. Evidence from studies that evaluate whether a clinical strategy guided by testing for SLCO1B1 or other genes involved in statin metabolism leads to improved patient outcomes does not exist.
Statins are associated with a definite decreased risk of cardiovascular events such as myocardial infarction, and this benefit of reduced cardiovascular events is likely to far outweigh the risk of myopathy, even in patients with the highest risk of myopathy, ie, 2 abnormal SLCO1B1 alleles. Therefore, there is a possibility of harm if the results of genetic testing for statin-induced myopathy are used as part of the decision-making process for prescribing statins. As a result, genetic testing for statin-induced myopathy is
considered not medically necessary.
Practice Guidelines and Position Statements
No guidelines or statements were identified.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
- Vladutiu GD. Genetic predisposition to statin myopathy. Curr Opin Rheumatol 2008; 20(6):648-55.
- Maggo SD, Kennedy MA, Clark DW. Clinical implications of pharmacogenetic variation on the effects of statins. Drug Saf 2011; 34(1):1-19.
- Pasternak RC, Smith SC, Jr., Bairey-Merz CN et al. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Circulation 2002; 106(8):1024-8.
- SEARCH Collaborative Group, Link E, Parish S et al. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med 2008; 359(8):789-99.
- McKenney JM, Davidson MH, Jacobson TA et al. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006; 97(8A):89C-94C.
- Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006; 97(8A):52C-60C.
- Wilke RA, Ramsey LB, Johnson SG et al. The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clin Pharmacol Ther 2012; 92(1):112-7.
- Schech S, Graham D, Staffa J et al. Risk factors for statin-associated rhabdomyolysis. Pharmacoepidemiol Drug Saf 2007; 16(3):352-8.
- Voora D, Shah SH, Spasojevic I et al. The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J Am Coll Cardiol 2009; 54(17):1609-16.
- Brunham LR, Lansberg PJ, Zhang L et al. Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin. Pharmacogenomics J 2012; 12(3):233-7.
- Brunham LR, Lansberg PJ, Zhang L et al. Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin. Pharmacogenomics J 2012; 12(3):233-7.
- Carr DF, O'Meara H, Jorgensen AL et al. SLCO1B1 genetic variant associated with statin-induced myopathy: a proof-of-concept study using the clinical practice research datalink. Clin Pharmacol Ther 2013; 94(6):695-701.
- Danik JS, Chasman DI, MacFadyen JG et al. Lack of association between SLCO1B1 polymorphisms and clinical myalgia following rosuvastatin therapy. Am Heart J 2013; 165(6):1008-14.
- de Keyser CE, Peters BJ, Becker ML et al. The SLCO1B1 c.521T>C polymorphism is associated with dose decrease or switching during statin therapy in the Rotterdam Study. Pharmacogenet Genomics 2014; 24(1):43-51.
- Ferrari M, Guasti L, Maresca A et al. Association between statin-induced creatine kinase elevation and genetic polymorphisms in SLCO1B1, ABCB1 and ABCG2. Eur J Clin Pharmacol 2014.
- Hoffman JM, Haidar CE, Wilkinson MR et al. PG4KDS: A model for the clinical implementation of pre-emptive pharmacogenetics. Am J Med Genet C Semin Med Genet 2014; 166(1):45-55.
|CPT||See Policy Guidelines|
|ICD-9-CM Diagnosis||359.24||Drug-induced myotonia|
|E947.1||Drugs causing adverse effects in therapeutic use; lipotropic drugs|
|ICD-10-CM (effective 10/1/15)||
|T46.6X5||Adverse effect of antihyperlipidemic and antiarteriosclerotic drugs|
|ICD-10-PCS (effective 10/1/15)||Not applicable. There are no ICD procedure codes for laboratory tests.|
Genetic Testing, SLCO1B1, Statin-Induced Myopathy
|6/13/13||Add to Medicine section||Policy created with literature search through May 15, 2013; genetic testing for the presence of variants in the SLCO1B1 gene for the purpose of identifying patients at risk of statin-induced myopathy is considered not medically necessary.|
|5/22/14||Replace policy||Policy updated with literature review through April 1, 2014;
references 9 and 12-16 added. Policy statement unchanged.