Book contents
- Frontmatter
- Contents
- Contributors
- Introduction
- I Critical Concepts
- II Therapeutic Areas
- 10 Oncologic Drugs
- 11 Pharmacogenetics and Pharmacogenomics of Cardiovascular Disease
- 12 Statin-Induced Muscle Toxicity
- 13 Genomics of the Drug-Induced Long-QT Syndrome
- 14 Pharmacogenetics of Diabetes
- 15 Pharmacogenetics – Therapeutic Area – Respiratory
- 16 Pharmacogenomics Associated with Therapy for Acid-Related Disorders
- 17 Pharmacogenetics of Rheumatology: Focus on Rheumatoid Arthritis
- 18 Pharmacogenetics of Obstetric Therapeutics
- 19 Pharmacogenomics of Psychiatric Drugs
- 20 Pain and Anesthesia
- 21 HIV and Antiretroviral Therapy
- 22 Application of Pharmacogenetics and Pharmacogenomics in Pediatrics: What Makes Children Different?
- References
12 - Statin-Induced Muscle Toxicity
from II - Therapeutic Areas
Published online by Cambridge University Press: 05 June 2012
Book contents
- Frontmatter
- Contents
- Contributors
- Introduction
- I Critical Concepts
- II Therapeutic Areas
- 10 Oncologic Drugs
- 11 Pharmacogenetics and Pharmacogenomics of Cardiovascular Disease
- 12 Statin-Induced Muscle Toxicity
- 13 Genomics of the Drug-Induced Long-QT Syndrome
- 14 Pharmacogenetics of Diabetes
- 15 Pharmacogenetics – Therapeutic Area – Respiratory
- 16 Pharmacogenomics Associated with Therapy for Acid-Related Disorders
- 17 Pharmacogenetics of Rheumatology: Focus on Rheumatoid Arthritis
- 18 Pharmacogenetics of Obstetric Therapeutics
- 19 Pharmacogenomics of Psychiatric Drugs
- 20 Pain and Anesthesia
- 21 HIV and Antiretroviral Therapy
- 22 Application of Pharmacogenetics and Pharmacogenomics in Pediatrics: What Makes Children Different?
- References
Summary
Introduction
β-Hydroxy-β-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are highly efficacious in the prevention of coronary artery disease. Although statins are generally considered safe, their use may be associated with musculoskeletal complaints that limit tolerance to treatment and, in the most extreme case, can lead to rhabdomyolysis. Both candidate gene and genome-wide association studies are being used to assess possible genetic susceptibility to statin-induced myopathy, with the recognition that this phenotype represents a broad spectrum of syndromes influenced by other drugs and disease states. In addition to potentially guiding statin therapy, the results of such studies may provide mechanistic insight into the critical cellular events linking statin use to muscle pathology in patients at risk.
Clinical Background
Multiple large clinical trials have demonstrated that statins (HMG-CoA reductase inhibitors) reduce the incidence of both primary and secondary coronary artery disease in patients at risk (1–4). Primary prevention trials have demonstrated that statin use can reduce the risk of a first major coronary event by more than 30 percent (3, 5). Secondary prevention trials reveal a risk reduction of similar magnitude (2). Aggressive intervention trials suggest that greater lipid lowering is associated with further reduction in risk (6).
- Type
- Chapter
- Information
- Principles of Pharmacogenetics and Pharmacogenomics , pp. 125 - 135Publisher: Cambridge University PressPrint publication year: 2012
References
Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study GroupN Engl J Med 1995 333 1301Google Scholar
Atorvastatin in the treatment of primary hypercholesterolemia and mixed dyslipidemiasAnn Pharmacother 1998 32 1030Google Scholar
JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive proteinN Engl J Med 2008 359 2195Google Scholar
Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary diseaseN Engl J Med 2005 352 1425Google Scholar
Lovastatin and beyond: the history of the HMG-CoA reductase inhibitorsNat Rev Drug Discov 2003 2 517Google Scholar
Risk for myopathy with statin therapy in high-risk patientsArch Intern Med 2003 163 553Google Scholar
Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)JAMA 2001 285 2486Google Scholar
An overview of the clinical safety profile of atorvastatin (Lipitor), a new HMG-CoA reductase inhibitorArch Intern Med 1998 158 577Google Scholar
Safety of HMG-CoA reductase inhibitors: focus on atorvastatinCardiovasc Drugs Ther 2001 15 211Google Scholar
Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task ForceAm J Cardiol 2006 97 89CGoogle Scholar
Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugsJAMA 2004 292 2585Google Scholar
Risk factors for statin-associated rhabdomyolysisPharmacoepidemiol Drug Saf 2007 16 352Google Scholar
Use of an electronic medical record to characterize cases of intermediate statin-induced muscle toxicityPrev Cardiol 2009 12 88Google Scholar
Rosuvastatin: a risk-benefit assessment for intensive lipid loweringExpert Opin Pharmacother 2005 6 1897Google Scholar
Identifying genetic risk factors for serious adverse drug reactions: current progress and challengesNat Rev Drug Discov 2007 6 904Google Scholar
Statin-associated myopathy with normal creatine kinase levelsAnn Intern Med 2002 137 581Google Scholar
Statin-associated myopathy with normal creatine kinase levelsAnn Intern Med 2003 138 1008Google Scholar
Differential association between statin exposure and elevated levels of creatine kinaseAnn Pharmacother 2005 39 1611Google Scholar
ACE ID genotype affects blood creatine kinase response to eccentric exerciseJ Appl Physiol 2007 103 2057Google Scholar
Statin and statin-fibrate use was significantly associated with increased myositis risk in a managed care populationJ Clin Epidemiol 2007 60 812Google Scholar
ACC/AHA/NHLBI clinical advisory on the use and safety of statinsCirculation 2002 106 1024Google Scholar
Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – The PRIMO studyCardiovasc Drugs Ther 2005 19 403Google Scholar
Clinical consequences of cytochrome P450 2C9 polymorphismsClin Pharmacol Ther 2005 77 1Google Scholar
Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damagePharmacogenet Genomics 2005 15 415Google Scholar
Effect of age and gender on pharmacokinetics of atorvastatin in humansJ Clin Pharmacol 1996 36 242Google Scholar
The role of cytochrome P450-mediated drug-drug interactions in determining the safety of statinsExpert Opin Pharmacother 2001 2 1119Google Scholar
Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazoleClin Pharmacol Ther 1998 63 332Google Scholar
New insights into the pharmacodynamic and pharmacokinetic properties of statinsPharmacol Ther 1999 84 413Google Scholar
Development and validation of a high-performance liquid chromatography tandem mass spectrometry assay for atorvastatin, ortho-hydroxy atorvastatin, and para-hydroxy atorvastatin in human, dog, and rat plasmaJ Am Soc Mass Spectrom 1999 10 55Google Scholar
Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatinClin Pharmacol Ther 2000 68 391Google Scholar
Is the cholesterol-lowering effect of simvastatin influenced by CYP2D6 polymorphism?Lancet 1997 350 29Google Scholar
Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatinClin Pharmacol Ther 2001 70 546Google Scholar
The efficacy of simvastatin is not influenced by CYP2D6 polymorphismClin Pharmacol Ther 2002 72 595Google Scholar
Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (-)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteersClin Pharmacol Ther 2003 74 186Google Scholar
Quantitation of the acid and lactone forms of atorvastatin and its biotransformation products in human serum by high-performance liquid chromatography with electrospray tandem mass spectrometryRapid Commun Mass Spectrom 1999 13 1003Google Scholar
Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapyPharmacoepidemiol Drug Saf 2004 13 417Google Scholar
Effects of fibrates on metabolism of statins in human hepatocytesDrug Metab Dispos 2002 30 1280Google Scholar
Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjectsBr J Clin Pharmacol 1990 29 239Google Scholar
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and rhabdomyolysis: considerations in the renal failure patientCurr Opin Nephrol Hypertens 2002 11 123Google Scholar
The pathway less traveled – moving from candidate genes to candidate pathways in the analysis of genome-wide data from large scale pharmacogenetic association studiesCurr Pharmacogenomics Pers Med 2008 6 150Google Scholar
Isoprenoids as mediators of the biological effects of statinsJ Clin Invest 2002 110 285Google Scholar
Molecular clues into the pathogenesis of statin-mediated muscle toxicityMuscle Nerve 2005 31 572Google Scholar
Analysis of the global RNA expression profiles of skeletal muscle cells treated with statinsJ Atheroscler Thromb 2005 12 121Google Scholar
2007
The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicityJ Clin Invest 2007 117 3940Google Scholar
Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgiaJ Pathol 2006 210 94Google Scholar
Statin-associated myopathy with normal creatine kinase levels. Case report from a Norwegian familyApmis 2005 113 635Google Scholar
High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trialClin Pharmacol Ther 2005 78 60Google Scholar
Evaluation of ubiquinone concentration and mitochondrial function relative to cerivastatin-induced skeletal myopathy in ratsToxicol Appl Pharmacol 2004 194 10Google Scholar
Effect of coenzyme Q(10) supplementation on Siwastatin-induced myalgiaAm J Cardiol 2007 100 1400Google Scholar
Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilonesProc Natl Acad Sci USA 1998 95 1369Google Scholar
7-Ketocholesterol-induced apoptosis – Involvement of several pro-apoptotic but also anti-apoptotic calcium-dependent transduction pathwaysFEBS J 2005 272 3093Google Scholar
Synchronization of tumor and normal cells from g-1 to multiple cell cycles by lovastatinCancer Res 1991 51 3602Google Scholar
Cell cycle arrest and apoptosis induction in hepatocellular carcinoma cells by HMG-CoA reductase inhibitors. Synergistic antiproliferative action with ligands of the peripheral benzodiazepine receptorJ Hepatol 2005 43 808Google Scholar
Statins activate GATA-6 and induce differentiated vascular smooth muscle cellsBiochem Biophys Res Commun 2008 374 731Google Scholar
GATA-6 mediates human bladder smooth muscle differentiation: involvement of a novel enhancer element in regulating beta-smooth muscle actin gene expressionAm J Physiol Cell Physiol 2007 293 C1093Google Scholar
Loss of both GATA4 and GATA6 blocks cardiac myocyte differentiation and results in acardia in miceDev Biol 2008 317 614Google Scholar
Highly coordinated gene regulation in mouse skeletal muscle regenerationJ Biol Chem. 2003 278 8826Google Scholar
A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in musclePLoS ONE 2006 1Google Scholar
Changes in ubiquitin proteasome pathway gene expression in skeletal muscle with exercise and statinsArterioscler Thromb Vasc Biol 2005 25 2560Google Scholar
Statins induce apoptosis in rat and human myotube cultures by inhibiting protein geranylgeranylation but not ubiquinoneToxicol Appl Pharmacol 2004 200 237Google Scholar
Effects of statins and farnesyltransferase inhibitors on the development and progression of cancerCancer Treat Rev 2004 30 609Google Scholar
The laminopathies: a clinical review [published correction appears inClin Genet 2007 71 293Google Scholar
Genetic risk factors associated with lipid-lowering drug-induced myopathiesMuscle Nerve 2006 34 153Google Scholar
Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kineticsClin Pharmacol Ther 2004 75 415Google Scholar
Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozilJ Pharmacol Exp Ther 2004 311 228Google Scholar
The effect of gemfibrozil on the pharmacokinetics of rosuvastatinClin Pharmacol Ther 2004 75 455Google Scholar
SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acidPharmacogenet Genomics 2006 16 873Google Scholar
SLCO1B1 variants and statin-induced myopathy – a genomewide studyN Engl J Med 2008 359 789Google Scholar
International economic analysis of primary prevention of cardiovascular disease with pravastatin in WOSCOPS. West of Scotland Coronary Prevention StudyEur Heart J 1999 20 263Google Scholar