General

Guideline Title

The Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update.

Bibliographic Source(s)

Ramsey LB, Johnson SG, Caudle KE, Haidar CE, Voora D, Wilke RA, Maxwell WD, McLeod HL, Krauss RM, Roden DM, Feng Q, Cooper-DeHoff RM, Gong L, Klein TE, Wadelius M, Niemi M. The Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther. 2014 Oct;96(4):423-8. [37 references] PubMed

Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Wilke RA, Ramsey LB, Johnson SG, Maxwell WD, McLeod HL, Voora D, Krauss RM, Roden DM, Feng Q, Cooper-Dehoff RM, Gong L, Klein TE, Wadelius M, Niemi M, Clinical Pharmacogenetics Implementation Consortium (CPIC). The Clinical Pharmacogenetics Implementation Consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clin Pharmacol Ther. 2012 Jul;92(1):112-7. [41 references]

This guideline meets NGC’s 2013 (revised) inclusion criteria.

Recommendations

Major Recommendations

The strength of therapeutic recommendations (Strong, Moderate, Optional) is defined at the end of the “Major Recommendations” field.

Genetic Test Interpretation

The assignment of the likely SLCO1B1 phenotype, based on * allele diplotypes, has been summarized in Table 1 below, based on rs4149056. SLCO1B1 alleles are often named using * allele nomenclature, representing various single-nucleotide polymorphisms (SNPs) alone or in combination (see Supplementary Table S1 online [see the “Availability of Companion Documents” field]) that are associated with low SLCO1B1 protein expression or function (see Supplementary Table S2 online [see the “Availability of Companion Documents” field]). The minor C allele at rs4149056 is contained within SLCO1B1*5 (rs4149056 alone) as well as the *15 and *17 haplotypes and is associated with lower plasma clearance of simvastatin. The magnitude of this effect is similar for the *5 , *15 , and *17 haplotypes. SLCO1B1 alleles have been extensively studied in multiple geographically, racially, and ethnically diverse groups. In general, rs4149056 is present at a minor allele frequency of between 5 and 20% in most populations (see Supplementary Tables S3 and S4 online [see the “Availability of Companion Documents” field]). Although all SLCO1B1 genetic tests interrogate rs4149056, other variants in this gene are also likely to be important, but their interpretation and application to statin prescribing is less clear. One of the limitations inherent in any genotype-only test is that very rare or de novo variants, which might have functional importance, will not generally be included.

Table 1. Assignment of Likely SLCO1B1 Phenotype Based on Genotype

Phenotype	Genotype Definition	Examples of Diplotypes	Genotype at rs4149056
Normal function; homozygous wild type or normal (55%–88% of patients ^a )	An individual carrying two normal-function alleles	1a/1a,1a/1b,1b/1b	TT
Intermediate function; heterozygous (11%–36% of patients ^a )	An individual carrying one normal-function allele plus one decreased-function allele	1a/5,1a/15,1a/17, 1b/5,1b/15,1b/17	TC
Low function; homozygous variant or mutant (0%–6% of patients ^a )	An individual carrying two decreased-function alleles	5/5,5/15,5/17, 15/15, 15/17, 17/17	CC

a Frequency of the polymorphism varies by ancestral group (Supplementary Tables S3 and S4 online [see the “Availability of Companion Documents” field]).

Therapeutic Recommendations

At the time of this writing, there are no data available regarding SLCO1B1 genotype effects on simvastatin response or myopathy in pediatric patients, and no data to show that the rs4149056 SNP in SLCO1B1 affects simvastatin’s disposition differently in children compared with adults.

Use of clinical decision support tools within electronic health records can assist clinicians in using genetic information to optimize drug therapy. Clinical implementation resources include workflow diagrams (see Supplementary Figures S2 and S3 online [see the “Availability of Companion Documents” field]), tables that translate genotype test results into an interpreted phenotype, example text for documentation in the electronic health record and point-of-care alerts, and cross-references for drug and gene names to widely used terminologies and standardized nomenclature systems (see Supplementary Tables S8–S12 online [see the “Availability of Companion Documents” field]).

Recommendations for Incidental Findings

Not applicable.

Table 2. Dosing Recommendations for Simvastatin Based on SLCO1B1 Phenotype

Phenotype	Implications for Simvastatin	Dosing Recommendations for Simvastatin ^a,b	Classification of Recommendations ^c
Normal function	Normal myopathy risk	Prescribe desired starting dose ^b and adjust doses of simvastatin based on disease-specific guidelines	Strong
Intermediate function	Intermediate myopathy risk	Prescribe a lower dose or consider an alternative statin (e.g., pravastatin or rosuvastatin); consider routine CK surveillance	Strong
Low function	High myopathy risk	Prescribe a lower dose or consider an alternative statin (e.g., pravastatin or rosuvastatin); consider routine CK surveillance	Strong

CK, creatine kinase.

a In all cases, the potential for drug–drug interaction should be evaluated before initiating a prescription.

b The U.S. Food and Drug Administration recommends against 80 mg (unless already tolerated for 12 months).

c See the Supplementary Material online (text section titled “Levels of Evidence” [see the “Availability of Companion Documents” field]) for additional details regarding the three-tiered system used to grade the quality of evidence.

Definitions:

Strength of Therapeutic Recommendations

Strong : The evidence is high quality and the desirable effects clearly outweigh the undesirable effects.

Moderate : There is a close or uncertain balance as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects.

Optional : The desirable effects are closely balanced with undesirable effects and there is room for differences of opinion as to the need for the recommended course of action.

Clinical Algorithm(s)

The following algorithms are provided in the supplementary material (see the “Availability of Companion Documents” field):

SLCO1B1 Pharmacogenetic Test Result: Clinical Implementation Workflow for EHR
SLCO1B1 Genotype and Simvastatin: Point of Care Clinical Decision Support

Scope

Disease/Condition(s)

Hypercholesterolemia and cardiovascular disease

Guideline Category

Prevention
Risk Assessment
Treatment

Clinical Specialty

Cardiology
Family Practice
Internal Medicine
Medical Genetics
Pharmacology
Preventive Medicine

Intended Users

Advanced Practice Nurses
Pharmacists
Physician Assistants
Physicians

Guideline Objective(s)

To update the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy
To summarize the current evidence from the literature and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype

Target Population

Patients who are on or who are being considered for simvastatin therapy

Interventions and Practices Considered

Simvastatin therapy and dosing adjustments based on SLCO1B1 genotype or phenotype

Note : Detailed guidelines for the use of simvastatin are beyond the scope of this article.

Major Outcomes Considered

Risk of adverse drug reactions, including statin-related muscle problems (e.g., myalgia, myopathy)
Premature discontinuation of statin medication
Higher low-density lipoprotein (LDL) cholesterol and cardiovascular risk

Methodology

Methods Used to Collect/Select the Evidence

Searches of Electronic Databases

Description of Methods Used to Collect/Select the Evidence

The authors searched the PubMed database (1966 to December 2013) and Ovid MEDLINE (1950 to December 2013) using several keyword strategies: SLCO1B1, SLCO1B1 AND myopathy, SLCO1B1 AND statin myopathy, SLCO1B1 AND simvastatin, SLCO1B1 AND LDL lowering, SLCO1B1 AND statin efficacy, SLCO1B1 AND statin kinetics AND human AND polymorphism, SLCO1B1 AND cardiovascular, OR SLCO1B1 AND statin uptake AND hepatocyte.

To construct tables showing SLCO1B1 (1966-May 2010) minor allele frequency based on ancestry, the PubMed database was further searched using the following criteria: SLCO1B1 , OATP1B1 , population, rs4149056, SLCO1B1*5 , SLCO1B1 *15. Studies were included if: ( A ) the race of the population was clearly indicated, ( B ) allele frequencies or minor allele percentages for SLCO1B1 haplotypes were reported, ( C ) the method by which SLCO1B1 was genotyped was reliable, ( D ) the sample size was at least 20 subjects.

Using the specified search criteria, 448 publications were identified (after excluding non-English manuscripts). Inclusion criteria included publications that included in vivo clinical outcome (i.e. lipid-lowering effects, myopathy and myalgia) for simvastatin in individuals who vary by SLCO1B1 genotype/phenotype, associations of SLCO1B1 genotype with simvastatin disposition in vitro, in vivo pharmacodynamic data for statins and SLCO1B1 genotype/phenotype, and in vivo pharmacokinetic data for simvastatin in individuals who vary by SLCO1B1 genotype/phenotype.

Number of Source Documents

Following application of the inclusion criteria, 25 publications were reviewed and included in the evidence table.

Methods Used to Assess the Quality and Strength of the Evidence

Weighting According to a Rating Scheme (Scheme Given)

Rating Scheme for the Strength of the Evidence

Levels of Evidence

High: Evidence includes consistent results from well-designed, well-conducted studies.

Moderate: Evidence is sufficient to determine the effects, but the strength of evidence is limited by the number, quality, or consistency of the individual studies; generalizability to routine practice; or indirect nature of the evidence.

Weak: Evidence is insufficient to assess the effects on health outcomes because of the limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information.

Methods Used to Analyze the Evidence

Review of Published Meta-Analyses
Systematic Review with Evidence Tables

Description of the Methods Used to Analyze the Evidence

The evidence summarized in Supplemental Table S5 (see the “Availability of Companion Documents” field) is graded using a scale based on previously published criteria and applied to other Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines (see the “Rating Scheme for the Strength of the Evidence” field).

Methods Used to Formulate the Recommendations

Expert Consensus

Description of Methods Used to Formulate the Recommendations

Overall, the therapeutic recommendations are simplified to allow rapid interpretation by clinicians. The Clinical Pharmacogenetics Implementation Consortium (CPIC) uses a slight modification of a transparent and simple system for just three categories for recommendations adopted from the rating scale for evidence-based recommendations on the use of retroviral agents (http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf) (see the “Rating Scheme for the Strength of Recommendations” field).

Rating Scheme for the Strength of the Recommendations

Strength of Therapeutic Recommendations

Strong : The evidence is high quality and the desirable effects clearly outweigh the undesirable effects.

Moderate : There is a close or uncertain balance as to whether the evidence is high quality and the desirable clearly outweigh the undesirable effects.

Optional : The desirable effects are closely balanced with undesirable effects and there is room for differences of opinion as to the need for the recommended course of action.

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation

Peer Review

Description of Method of Guideline Validation

Not stated

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is identified and graded for each recommendation (see the “Major Recommendations” field).

Every effort was made to present evidence from high-quality studies, which provided the framework for the strength of therapeutic recommendations.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Based on the highly prevalent use of simvastatin, a potential benefit of preemptive SLCO1B1 testing is a significant reduction in the incidence of simvastatin-induced myopathies and rhabdomyolysis, by identifying those at significant risk and recommending a lower simvastatin dose or an alternative statin as appropriate.
In addition, genotyping may promote statin adherence and lower low-density lipoprotein (LDL) cholesterol levels.

Potential Harms

The most common statin-related adverse drug reaction (ADR) is skeletal muscle toxicity. Statin-related muscle problems include myalgias (pain without evidence of muscle degradation), myopathy (pain with evidence of muscle degradation), and rhabdomyolysis (severe muscle damage with acute kidney injury). Frequency varies by definition; but, overall, statin-related myalgias are common, occurring in 1% to 5% of exposed subjects.
A possible risk could be an error in genotyping. Since genotypes are lifelong test results, any such error could stay in the medical record for the life of the patient. An error in genotyping could result in a decrease in simvastatin dose that was not otherwise necessary and could result in inadequate lipid-lowering therapy.
Another potential risk to pre-emptive genotyping is that a patient’s knowledge of a genetic profile associated with a high risk of adverse events may lead the patient to associate unrelated adverse events (i.e., nonspecific myalgias/arthralgias) to his/her statin therapy. If a patient then prematurely discontinues his/her statin and/or the physician reduces the dose, this may result in higher low-density lipoprotein (LDL) cholesterol and cardiovascular risk.

Qualifying Statements

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written, and are intended only to assist clinicians in decision making, as well as to identify questions for further research. New evidence may have emerged since the time a guideline was submitted for publication. Guidelines are limited in scope and are not applicable to interventions or diseases that are not specifically identified. Guidelines do not account for all individual variations among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for the patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application being solely made by the clinician and the patient. CPIC assumes no responsibility for any injury to people or damage to property related to any use of CPIC’s guidelines, or for any errors or omissions.

Caveats: Appropriate Use and/or Potential Misuse of Genetic Tests

For the 40-mg simvastatin dose, the relative risk of myopathy is 2.6 per copy of the C allele at rs4149056. The risk is higher for the 80-mg simvastatin dose (myopathy OR 4.5 for TC genotype, ~20.0 for CC genotype). Nonetheless, simvastatin-related muscle toxicity can still occur in the absence of rs4149056. Thus, a TT genotype does not imply the absence of another potentially deleterious variant in SLCO1B1 or elsewhere. Further, because rs4149056 can also be inherited in combination with other SLCO1B1 gene variants known to have protective effects, it should not be presumed that the C allele at rs4149056 confers risk with 100% certainty.

Implementation of the Guideline

Description of Implementation Strategy

Use of clinical decision support tools within electronic health records (EHRs) can assist clinicians in using genetic information to optimize drug therapy. Clinical implementation resources include workflow diagrams (Supplementary Figures S2 and S3 online [see the “Availability of Companion Documents” field]), tables that translate genotype test results into an interpreted phenotype, example text for documentation in the EHR and point-of-care alerts, and cross-references for drug and gene names to widely used terminologies and standardized nomenclature systems (Supplementary Tables S8–S12 online [see the “Availability of Companion Documents” field]).

Implementation Tools

Clinical Algorithm
Resources

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need

Getting Better

IOM Domain

Effectiveness
Safety

Identifying Information and Availability

Bibliographic Source(s)

Ramsey LB, Johnson SG, Caudle KE, Haidar CE, Voora D, Wilke RA, Maxwell WD, McLeod HL, Krauss RM, Roden DM, Feng Q, Cooper-DeHoff RM, Gong L, Klein TE, Wadelius M, Niemi M. The Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther. 2014 Oct;96(4):423-8. [37 references] PubMed

Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released

2012 Jul (revised 2014 Oct)

Guideline Developer(s)

Clinical Pharmacogenetics Implementation Consortium - Independent Expert Panel

Source(s) of Funding

This work was funded by the National Institutes of Health (NIH)/National Institute of General Medical Science (PAAR4Kids [UO1 GM92666] and PharmGKB [R24 GM61374]). The following NIH grant support is acknowledged: U01 HL0105918, U01HL069757 (R.M.K), U19HL065962 (D.M.R.), U01HG006378 (D.M.R.), U01GM074492 and U01HG007269 (R.M.C.-D.), R01 HL118049 (D.V.), and R24 GM61374 (L.G. and T.E.K.). M.W. is supported by the Swedish Research Council (Medicine 523-2008-5568 and 521-2011-2440), the Swedish Heart and Lung Foundation, and the Clinical Research Support (ALF) at Uppsala University. M.N. has grants from the Sigrid Jusélius Foundation (Helsinki, Finland), the Helsinki University Central Hospital (Helsinki, Finland), and the European Research Council (Brussels, Belgium). D.V. is also supported by the Department of Defense (FA8650-13-2-6375). The funding organizations played no role in the writing of these guidelines.

Guideline Committee

Not stated

Composition of Group That Authored the Guideline

Authors : LB Ramsey, Pharmaceutical Sciences Department, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA; SG Johnson, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver, Colorado, USA, Clinical Pharmacy Services, Kaiser Permanente Colorado, Denver, Colorado, USA; KE Caudle, Pharmaceutical Sciences Department, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA; CE Haidar, Pharmaceutical Sciences Department, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA; D Voora, Department of Medicine, Duke University, Durham, North Carolina, USA; RA Wilke, IMAGENETICS, Sanford Medical Center, Fargo, North Dakota, USA, Department of Medicine, University of North Dakota, Fargo, North Dakota, USA; WD Maxwell, Department of Clinical Pharmacy and Outcomes Sciences, South Carolina College of Pharmacy, Columbia, South Carolina, USA; HL McLeod, Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida, USA; RM Krauss, Atherosclerosis Research, Children’s Hospital Oakland Research Institute, Oakland, California, USA; DM Roden, Oates Institute for Experimental Therapeutics, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Q Feng, Oates Institute for Experimental Therapeutics, Vanderbilt University Medical Center, Nashville, Tennessee, USA, Department of Medicine, Division of Clinical Pharmacology, Vanderbilt; University, Nashville, Tennessee, USA; RM Cooper-DeHoff, Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida, USA; L Gong, Department of Genetics, Stanford University, Palo Alto, California, USA; TE Klein, Department of Genetics, Stanford University, Palo Alto, California, USA; M Wadelius, Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; and M Niemi, Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland, King Abdulaziz University, Jeddah, Saudi Arabia

Financial Disclosures/Conflicts of Interest

D. Voora is a consultant for RenaissanceRx and has funding through the Department of Defense supporting an ongoing clinical trial of genotype-guided statin therapy (NCT01894230). The other authors declared no conflict of interest.

Guideline Status

This is the current release of the guideline.

This guideline meets NGC’s 2013 (revised) inclusion criteria.

Guideline Availability

Available from the Clinical Pharmacogenetics Implementation Consortium (CPIC) Web site.

Availability of Companion Documents

The following are available:

Supplementary material, including tables and methodological information, is available from the Clinical Pharmacogenetics Implementation Consortium (CPIC) Web site.
Statin pharmacokinetic and pharmacodynamic pathways are available from the CPIC Web site.
A 2014 SLCO1B1 translation table is available from the CPIC Web site.

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on May 15, 2013. The information was verified by the guideline developer on June 25, 2013. This summary was updated by ECRI Institute on December 4, 2014. The updated information was verified by the guideline developer on January 23, 2015.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the guideline developer’s copyright restrictions.

CPIC® is a registered service mark of the U.S. Department of Health & Human Services (HHS).

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