SLCO1B1 and Statin Therapy
2018; Wolters Kluwer; Volume: 11; Issue: 9 Linguagem: Inglês
10.1161/circgen.118.002320
ISSN2574-8300
Autores Tópico(s)Health Systems, Economic Evaluations, Quality of Life
ResumoHomeCirculation: Genomic and Precision MedicineVol. 11, No. 9SLCO1B1 and Statin Therapy Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSLCO1B1 and Statin TherapyGetting the GIST of Pharmacogenetic Testing Sony Tuteja, PharmD, MS and Daniel J. Rader, MD Sony TutejaSony Tuteja Sony Tuteja, PharmD, MS, Division of Translational Medicine and Human Genetics, Department of Medicine, Smilow Center for Translational Research, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Bldg 421, 11th Floor, Room 143, Philadelphia, PA 19104. Email E-mail Address: [email protected] Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (S.T, D.J.R) and Daniel J. RaderDaniel J. Rader Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia (S.T, D.J.R) Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia (D.J.R.) Originally published17 Sep 2018https://doi.org/10.1161/CIRCGEN.118.002320Circulation: Genomic and Precision Medicine. 2018;11:e002320This article is a commentary on the followingEffects of Delivering SLCO1B1 Pharmacogenetic Information in Randomized Trial and Observational SettingsSee Article by Peyser et alStatins are the most widely prescribed lipid-lowering therapies for the treatment and prevention of cardiovascular disease.1 Statins are generally safe and well tolerated in most individuals; however, they are associated with muscle toxicity which can range in spectrum from mild myalgia without an elevation in creatine kinase to rare life-threatening autoimmune necrotizing myositis.2 Although randomized controlled trials report similar adverse event rates, including muscle pain, between statin and placebo groups,3 observational and patient registry studies report a 7% to 29% incidence of statin-associated muscle symptoms (SAMS).4–6 Milder forms of SAMS are self-limiting; however, they are frequently a cause of statin nonadherence and drug discontinuation.5,6 Statin nonadherence and discontinuations have been associated with a higher rate of cardiovascular events and death.7 Recent cholesterol guidelines from the American Heart Association/American College of Cardiology expands the population eligible to receive statins even though they might not have clinically overt cardiovascular disease,1 thereby increasing the number of patients potentially at risk for SAMS.Genetic determinants of drug response and adverse drug reactions are well known. The application of genetic information to individualize drug treatments to maximize efficacy and avoid adverse events, or pharmacogenetics, is an important component of precision medicine. A genetic contribution to SAMS was identified through a genome-wide association study of patients with myopathy while taking high-dose simvastatin. Heterozygous and homozygous carriers of the C variant at rs4149056 (*5) in the solute carrier anion transporter family 1B1 (SLCO1B1) gene had an odds ratio for myopathy of 4.5 (95% confidence interval, 4.7–61.1) and 17 (95% confidence interval, 4.7–61.1), respectively, when compared with the TT homozygotes.8 The *5 variant is associated with reduced activity of the hepatic OATP1B1 (organic anion-transporting polypeptide) transporter and increased plasma concentrations of simvastatin.9 Polymorphisms in SLCO1B1 are also implicated in milder forms of statin intolerance.10 However, it is unknown whether prospective pharmacogenetic testing would improve outcomes for patients receiving statin treatment. Because the risk of SAMS with the *5 allele is greatest with simvastatin and the least with pravastatin or rosuvastatin,11 clinical pharmacogenetic testing for SLCO1B1*5 provides an opportunity for tailoring statin therapy based on genetics. Clinical implementation of pharmacogenetic testing before statin initiation has been challenging because of a wide therapeutic index of statins, availability of low-cost statin alternatives to simvastatin, and difficulty in defining myalgias in practice. In this issue, Peyser et al12 examine whether providing SLCO1B1 genetic information to primary care providers and patients with a history of statin side effects would improve medication adherence on statin reinitiation.Peyser et al12 randomized 159 patients with a history of statin-induced side effects to receive SLCO1B1 genotype-informed statin therapy (GIST) or usual care. Patients in the usual care arm received their SLCO1B1 results at the end of the 8-month study period. Test results and statin dosing recommendations were returned to primary care providers within the electronic health record with minimal disruption to the clinical workflow. Rosuvastatin, pravastatin, or fluvastatin was recommended for SLCO1B1*5 carriers, whereas noncarriers were recommended to rechallenge with any statin that had not been tried in the past. The primary outcome was statin adherence using the Morisky Medication Adherence Scale, assessed in patients reinitiating statins. Secondary outcomes included the number of patients reinitiating statins, LDL-C (low-density lipoprotein cholesterol) levels, and patient's perceptions of statin therapy. The authors also examined LDL-C levels in 1907 patients receiving SLCO1B1 testing from a commercial laboratory compared with propensity-matched untested controls.Among the trial participants, 25% were SLCO1B1*5 carriers, a frequency greater than typically found in European ancestry individuals (16.5%). Statin adherence as determined by the Morisky Medication Adherence Scale was similar between the 2 arms; thus, no difference was observed in the primary outcome. However, GIST led to more new statin prescriptions compared with the usual care group (55.4% versus 38.0%; P=0.04), lower LDL-C levels at 3 months (131.9±42.0 versus 144.4±43.0 mg/dL; P=0.04), and numerically lower levels at 8 months (128.6±37.9 versus 141.0±44.4; P=0.12). After the trial, LDL-C decreased in the usual care participants who subsequently received the results of the SLCO1B1 testing compared with those originally allocated to the GIST group (−14.9±37.8 versus 9.0±37.3 mg/dL; P=0.048). Patients allocated to GIST had a trend toward improvement in statin perceptions as assessed by the Beliefs in Medication Questionnaire. Their findings about the impact of genetic testing on LDL-C levels were validated with observational data from patients undergoing SLCO1B1 testing in a commercial laboratory, who experienced a greater decrease in LDL-C levels compared with matched, untested controls.Peyser et al12 have performed the first prospective randomized SLCO1B1 genotype-guided study for statin reinitiation. Although they failed to show that genotyping improved statin adherence, they did show that genotyping led to a greater number of patients reinitiated on statins and meaningful improvements in LDL-C levels. Although SLCO1B1 genotyping increased the number of patients reinitiated on statins, the overall rate of statin reinitiation in the trial (39%) was lower than expected based on the authors' prior work (60%), which reduced the power for the primary end point. The absolute difference in the Morisky Medication Adherence Scale was 0.1 points (95% confidence interval, −1.0 to 0.73) with clinically meaningful differences observed with a change of 2 points. Therefore, larger sample sizes would not have changed the primary conclusion that SLCO1B1 genotyping does not improve self-reported statin adherence. The authors acknowledge that poor medication adherence has multifactorial causes and will likely require a multipronged sustained effort to influence a patient's medication-taking behavior.13 Genotyping will serve to increase the number of patients considered for statin reinitiation; however, maintaining patients on statins will require complementary interventions to address barriers to medication adherence such as patient education by allied health professionals and digital reminders.14Through assessment of prespecified secondary end points, Peyser et al12 confirm that SAMS is a significant barrier to reducing cardiovascular risk. Performing SLCO1B1 testing led to an increased willingness by providers to reinitiate statins and improved patient perceptions of statin therapy. This translated into a 20 mg/dL reduction in LDL-C levels during the trial in the GIST group and a 14.9 mg/dL reduction in the usual care group that received the pharmacogenetic test results at the end of the trial. Agreement to the genotype-guided intervention, defined by proportion of SLCO1B1*5 carriers prescribed rosuvastatin, pravastatin, or fluvastatin versus other statins, was numerically greater in the intervention group (92% versus 67%, P=0.24). Interestingly, SLCO1B1*5 carriers had a greater decrease in LDL-C with genetic testing versus usual care, implying that delivering an actionable test result with specific pharmacotherapy prescribing recommendations led to a greater effect than delivering a negative result where no action is required.We commend the authors on performing a randomized controlled trial for SLCO1B1 testing as the challenges in performing such studies are considerable. Widespread adoption of clinical pharmacogenetics has been hampered by the lack of clinical utility trials showing improved outcomes and cost-effectiveness in patients undergoing pharmacogenetic testing. Controversy exists on the level of evidence required for clinical implementation of pharmacogenetic testing.15,16 Rigorous, randomized outcomes trials are desired by groups such as the American Heart Association (as demonstrated by their stance in the case of CYP2C19-clopidogrel17) which generates evidence-based guidelines as well as third-party payers making reimbursement decisions. Studies such as the one conducted by Peyser et al12 will serve to move pharmacogenetics one step closer to clinical care.Proponents of pharmacogenetic testing suggest that a randomized controlled trial cannot be performed for every gene-drug pair because of undue cost, rarity of risk alleles, and ethical concerns.16 This is true in the example of carbamazepine-induced life-threatening cutaneous adverse reaction in carriers of rare HLA *15:02 and *31:01 alleles (minor allele frequency in European ancestry individuals of 0.0004 and 0.0284, respectively).18 Several healthcare centers have moved forward with clinical testing of pharmacogenetics variants where the preponderance of data strongly links genotype to drug response phenotypes. Clinical implementation efforts have been aided by the National Institutes of Health–funded Clinical Pharmacogenetics Implementation Consortium which has published peer-reviewed guidelines for 30 gene-drug pairs (https://cpicpgx.org), including SLCO1B1-simvastatin, translating pharmacogenetics test results into actionable prescribing decisions for clinicians.19 It is important to note that for even for well-studied pharmacogenetic variants, they do not explain all the variation in drug effects. Therefore, pharmacogenetics is not the magic arrow to guarantee a positive drug-related outcome, but an important instrument to get us closer to the target.The study by Peyser et al12 demonstrated that genotype-guided statin reinitiation led to several clinical benefits without significant harms. Their study also highlights the challenges and barriers of delivering pharmacogenetics in a clinical setting. Factors beyond the gene-drug relationship will impact widespread test adoption such as stakeholder acceptance of pharmacogenetics, provider and patient education, optimal messaging of pharmacogenetic pharmacotherapy recommendations, and robust information technology infrastructure.20 Continued accumulation of evidence surrounding clinical utility of pharmacogenetic testing is crucial as this will inform reimbursement policy and drive adoption of pharmacogenetics into routine care. Parallel efforts that enable the implementation of these discoveries in clinical care are also needed to optimize therapeutic outcomes.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circgenSony Tuteja, PharmD, MS, Division of Translational Medicine and Human Genetics, Department of Medicine, Smilow Center for Translational Research, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Blvd, Bldg 421, 11th Floor, Room 143, Philadelphia, PA 19104. Email [email protected]upenn.eduReferences1. 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Opportunities to implement a sustainable genomic medicine program: lessons learned from the ignite network [published online July 12, 2018].Genet Med. doi: 10.1038/s41436-018-0080-y. https://www.nature.com/articles/s41436-018-0080-y. Accessed September 6, 2018.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Belanger M, Kelly E, Tahir U and Benson M (2021) Genetic Risk Assessment for Atherosclerotic Cardiovascular Disease: A Guide for the General Cardiologist, Cardiology in Review, 10.1097/CRD.0000000000000384, 30:4, (206-213), Online publication date: 1-Jul-2022. Psarias G, Iliopoulou E, Liopetas I, Tsironi A, Spanos D, Tsikrika A, Kalafatis K, Tarousi D, Varitis G, Koromina M, Siamoglou S and Patrinos G (2020) Development of Rapid Pharmacogenomic Testing Assay in a Mobile Molecular Biology Laboratory (2MoBiL), OMICS: A Journal of Integrative Biology, 10.1089/omi.2020.0168, 24:11, (660-666), Online publication date: 1-Nov-2020. Sivashanmugarajah A, Fulcher J, Sullivan D, Elam M, Jenkins A and Keech A (2020) Author reply, Internal Medicine Journal, 10.1111/imj.14785, 50:4, (507-508), Online publication date: 1-Apr-2020. Related articlesEffects of Delivering SLCO1B1 Pharmacogenetic Information in Randomized Trial and Observational SettingsBruce Peyser, et al. Circulation: Genomic and Precision Medicine. 2018;11 September 2018Vol 11, Issue 9 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.118.002320PMID: 30354338 Originally publishedSeptember 17, 2018 Keywordsdrug-related side effects and adverse reactionsEditorialspharmacogeneticsmyalgiasimvastatinmyositisPDF download Advertisement SubjectsClinical StudiesCompliance/AdherenceGeneticsLipids and CholesterolPharmacology
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