Medical Policy

 

Subject: Genetic Testing for Statin-Induced Myopathy
Document #: GENE.00038 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    05/04/2017

Description/Scope

This document addresses genetic testing for predicting the risk of myopathy in individuals being treated or considered for treatment with statin therapy. Statin drugs are the primary pharmacologic treatment for hypercholesterolemia to reduce cardiovascular morbidity and mortality. Despite their proven efficacy, many individuals with cardiovascular disease (CVD) are nonadherent with statin medications due to medication-induced side effects, including statin-associated myalgia, myopathy, and more rarely, severe muscle damage with associated acute kidney injury. Specific genetic factors appear to increase the risk of statin-induced myopathy.

Position Statement

Investigational and Not Medically Necessary:

Genetic testing for the presence of variants in the SLCO1B1 gene to identify individuals at increased risk of statin-induced myopathy is considered investigational and not medically necessary.

Rationale

The body of evidence regarding the use of genetic testing to assess the risk of statin-induced myopathy is sparse and of low quality. In particular, studies that evaluate the clinical validity and clinical utility of genetic testing for statin-induced myopathy are lacking.

Several studies were identified in the peer-reviewed literature that assessed the level of risk for myopathy associated with SLCO1B1 gene variants; some of these studies reported moderate to strong statistical associations between these two variables. In particular, for simvastatin, there is evidence from randomized controlled trials (RCTs) and prospective cohort studies demonstrating statistical associations of statin-induced myopathy with SLCO1B1 gene polymorphisms (de Keyser, 2014; Ferrari, 2014; Hou, 2015; Ramsey, 2014; The SEARCH Collaborative Group, 2008). However, there is also conflicting evidence from large cohort studies in which no statistical association was found between statin-induced (simvastatin and atorvastatin) myopathy and SLCO1B1 gene polymorphisms (Ginnakopoulou, 2014; Hubáček, 2015; Li, 2015) (n=386; n=3008; n=3049, respectively).

In 2014, the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines were developed to assist in the clinical management of myopathy risk in individuals on statin therapy. According to guideline authors, the strength of the evidence is highest for simvastatin relative to other statin types. The guideline recommendations state that for individuals with the C allele at SLCO1B1 (rs4149056), there are modest increases in the risk of myopathy at lower doses of simvastatin (40 mg daily), and as such, if optimal efficacy cannot be achieved with the lower dose of medication, alternate agents should be considered. The CPIC limits their recommendations to only simvastatin (Ramsey, 2014).

In 2013, the American College of Cardiology (ACC)/American Heart Association (AHA) published updated clinical guidelines for the treatment of blood cholesterol in individuals at high risk of CVD. The intensity of statin therapy was the goal of treatment used in this guideline. The guidelines recommended statin therapy for four major groups of individuals for whom statins have the greatest chance of preventing stroke and myocardial infarction: (1) Individuals with clinical atherosclerotic CVD (ASCVD); (2) Individuals with primary elevations of low-density lipoprotein cholesterol (LDL-C); (3) Individuals 40 to 75 years of age with diabetes and elevated LDL-C, without clinical ASCVD; and (4) Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age with elevated LDL–C and a 10-year ASCVD risk of ≥ 7.5%. The ACC/AHA guidelines do not include genotype as a recommendation for consideration of determining the safety and efficacy of statin-based therapy.

In 2016, Leusink and colleagues conducted a systematic review of evidence for pharmacogenetic associations with statins based on 17 years of evidence. A total of 173 articles met inclusion criteria. The outcomes of interest were modification of LDL-C levels and modification of risk for CVD events. From the review, a total of 141 loci were identified that were purported to be associated with LDL-C lowering, only 5% of which were found to have been replicated. In addition, six single nucleotide polymorphisms (SNPs) were identified to have a significant association with LDL-C response, one of which was SLCO1B1; however, none consistently reduced the likelihood of a CVD event. The authors concluded that, although SLCO1B1 and a handful of other genetic loci are consistently associated with LDL-C, effect sizes are too modest to conclude that there is value added through genetic testing in cardiology clinical practice.

In general, clinical studies are lacking that identify a favorable net clinical outcome from managing statin use through treatment modification using this genetic test. Moreover, some investigators have posited that when statin use is reduced or eliminated as a result of genetic testing, the increased risk of cardiovascular events may outweigh the reduced risk of statin-induced myopathy. Well-designed clinical studies elucidating the net clinical benefit and overall clinical utility of genetic testing to assess the risk of statin-induced myopathy are warranted (Stewart, 2013).

Background/Overview

Statin drugs are the primary pharmacologic treatment for hypercholesterolemia and coronary artery disease (CAD) worldwide. Their use is associated with an approximate 30% reduction in cardiovascular events and they are the most commonly prescribed medications in the United States.

Despite their demonstrated safety and efficacy, 25% to 50% of individuals with CVD are nonadherent with statin medications after 1 year. Although there may be multiple contributing factors, many experts report that a contributor to statin nonadherence is associated side effects from this class, including skeletal muscle toxicity due to poor or compromised metabolism of statin drugs. It has been reported in clinical trials that 1% to 5% of subjects develop statin-associated muscle pain (myalgia), with approximately 1 in 1000 experiencing muscle degradation (myopathy), and 1.6 in 100,000 suffering from severe muscle damage with associated acute kidney injury (rhabdomyolysis). Myositis is much less common than myalgia, with an estimated per-person incidence of 0.01%. These complications have been reported to negatively impact compliance, tolerability, and quality of life (QOL) in individuals taking statins (Harper, 2010; Ramsey, 2014; Stone, 2013).

Genetic factors appear to increase the risk of statin-induced myopathy in certain populations. Clinical studies have demonstrated a statistical association between statin-induced myopathy and specific variations in the SLCO1B1 gene. Additional studies have demonstrated that individuals who have inherited variations on the SLCO1B1 gene are significantly more likely to suffer myopathy as a side effect of statin medications. Inherited variations in the SLCO1B1 gene may result in reduced effectiveness of statin therapy and increased risk of myopathy. In particular, a genome-wide association study demonstrated that common variants of the SLCO1B1 gene significantly increased or decreased the risk of myopathy in individuals treated with simvastatin (Stewart, 2013).

Commercial genetic tests performed on blood samples to identify the presence of SLCO1B1 gene variants have been proposed as a means of predicting the risk of myopathy in individuals on statin therapy for CVD. Commercial tests for SLCO1B1 use allele-specific polymerase chain reaction (PCR) and high-resolution melting (HRM) analysis to identify genetic variants on the SLCO1B1 gene. One commercially available test is the Boston Heart DiagnosticsTM (Framingham, MA) Statin Induced Myopathy (SLCO1B1) Genotype test (Harper, 2010; Ramsey, 2014).

Genetic testing for statin-induced myopathy is not subject to federal regulation by the U.S. Food and Drug Administration (FDA). Genetic tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA) Act of 1988. Premarket approval by the FDA is not required provided the assay is performed in a laboratory facility that observes CLIA regulations.

Definitions

Genetic polymorphism: Recurrence within a population of two or more discontinuous genetic variants of a specific trait in such proportions that they cannot be maintained only by mutation.

Hypercholesterolemia: High levels of blood cholesterol.

Myositis: Inflammation of the muscles.

Statin: A drug that inhibits the synthesis of cholesterol and promotes the production of low density lipoprotein (LDL)-binding receptors in the liver resulting in an unusually marked decrease in the level of LDL, and a modest increase in the level of high density lipoprotein (HDL) circulating in blood plasma.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
For the following procedure and diagnosis codes, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

 

81328

SLCO1B1 (solute carrier organic anion transporter family, member 1B1) (eg, adverse drug reaction), gene analysis, common variant(s) (eg, *5)

 

 

 

 

ICD-10 Diagnosis

 

 

All diagnoses

References

Peer Reviewed Publications:

  1. 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.
  2. Drobny M, Pullmann R, Odalos I, et al. Incidence of skeletal muscle disorders after statins' treatment: consequences in clinical and EMG picture. Neuro Endocrinol Lett. 2014; 35(2):123-128.
  3. 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; 70(5):539-547.
  4. Giannakopoulou E, Ragia G, Kolovou V, et al. No impact of SLCO1B1 521T>C, 388A>G and 411G>A polymorphisms on response to statin therapy in the Greek population. Mol Biol Rep. 2014; 41(7):4631-4638.
  5. Harper CR, Jacobson TA. Evidence-based management of statin myopathy. Curr Atheroscler Rep. 2010; 12:322-330.
  6. Hou Q, Li S, Li L, et al. Association between SLCO1B1 gene T521C polymorphism and statin-related myopathy risk: a meta-analysis of case-control studies. Medicine (Baltimore). 2015; 94(37):e1268.
  7. Hubáček JA, Dlouhá D, Adámková V, et al. SLCO1B1 polymorphism is not associated with risk of statin-induced myalgia/myopathy in a Czech population. Med Sci Monit. 2015; 21:1454-1459.
  8. Leusink M, Onland-Moret NC, de Bakker PI, et al. Seventeen years of statin pharmacogenetics: a systematic review. Pharmacogenomics. 2016; 17(2):163-180.
  9. Li JH, Suchindran S, Shah SH, SLCO1B1 genetic variants, long-term low-density lipoprotein cholesterol levels and clinical events in patients following cardiac catheterization. Pharmacogenomics. 2015; 16(5):449-458.
  10. Ramsey LB, Johnson SG, Caudle KE, et al. The Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1and simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther. 2014; 96(4):423-428.
  11. Stewart A. SLCO1B1 polymorphisms and statin-induced myopathy. PLoS Curr. 2013; 5. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871416/?report=printable. Accessed on March 09, 2017.
  12. The SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy-a genome wide study. N Engl J Med. 2008; 359(8):789-799.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129(25 Suppl 2):S1-S45. Available at: http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a. Accessed on March 09, 2017.
  2. Woolley T, Canoniero M, Conroy W, et al. Institute for Clinical Systems Improvement (ICSI). Lipid Management in Adults. Updated November 2013. Available at: https://www.icsi.org/_asset/qz5ydq/LipidMgmt-Interactive1111.pdf . Accessed on March 09, 2017.
Websites for Additional Information
  1. National Library of Medicine (NLM). Genetic Home Reference. SLCO1B1. Reviewed March 2013. Available at: http://ghr.nlm.nih.gov/gene/SLCO1B1. Accessed on March 09, 2017.
Index

SLCO1B1

 The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
  12/27/2017

The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Coding section with 01/01/2018 CPT changes; added code 81328 replacing Tier 2 code 81400.

Reviewed 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.  Updated Rationale and References sections.
Reviewed 05/05/2016 MPTAC review. Updated Rationale and Reference sections. Removed ICD-9 codes from Coding section.
Reviewed 05/07/2015 MPTAC review. Updated Description/Scope, Rationale, Background/Overview, Definitions and Reference sections.
New 05/15/2014 MPTAC review. Initial document development.