Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care.
Marianne K. DeGorter,Rommel G. Tirona,Ute I. Schwarz,Yun-Hee Choi,George K. Dresser,Neville Suskin,Kathryn Myers,Guangyong Zou,Otito Iwuchukwu,Wei-Qi Wei,Russell A. Wilke,Robert A. Hegele,Richard B. Kim +12 more
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TLDR
Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms, and an algorithm incorporating genomic and clinical variables to avoid high atorVastatin and rosuvastatin levels is described.Abstract:
Background— A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients.
Methods and Results— In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for sex, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T>C ( P A ( P G ( P C ( P <0.05) and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R 2=0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient’s risk–benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile.
Conclusions— Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine whether this approach reduces incidence of statin myopathy.read more
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Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management
Erik S.G. Stroes,Paul D. Thompson,Alberto Corsini,Georgirene D. Vladutiu,Frederick J. Raal,Kausik K. Ray,Michael Roden,Evan A. Stein,Lale Tokgozoglu,Børge G. Nordestgaard,Eric Bruckert,Guy De Backer,Ronald M. Krauss,Ulrich Laufs,Raul D. Santos,Robert A. Hegele,G. Kees Hovingh,Lawrence A. Leiter,François Mach,Winfried März,Connie B. Newman,Olov Wiklund,Terry A. Jacobson,Alberico L. Catapano,M. John Chapman,Henry N. Ginsberg +25 more
TL;DR: The Panel proposes to identify SAMS by symptoms typical of statin myalgia and their temporal association with discontinuation and response to repetitive statin re-challenge, and recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets.
Journal ArticleDOI
The pharmacology of statins.
TL;DR: The impact of the antagonism of statins on a crucial step of intermediary metabolism leads, in fact, both to a reduction of cholesterol biosynthesis as well as to additional pharmacodynamic effects, which are unlikely to change.
Journal ArticleDOI
The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 and Simvastatin‐Induced Myopathy: 2014 Update
Laura B. Ramsey,S G Johnson,S G Johnson,Kelly E. Caudle,Cyrine E. Haidar,Deepak Voora,R. A. Wilke,Whitney D. Maxwell,Howard L. McLeod,Ronald M. Krauss,Dan M. Roden,Dan M. Roden,QiPing Feng,QiPing Feng,Rhonda M. Cooper-DeHoff,Li Gong,Teri E. Klein,Mia Wadelius,Mikko Niemi,Mikko Niemi +19 more
TL;DR: Evidence from the literature supporting a single coding single‐nucleotide polymorphism in SLCO1B1 increases systemic exposure to simvastatin and the risk of muscle toxicity and therapeutic recommendations are provided.
Journal ArticleDOI
Adverse effects of statin therapy: perception vs. the evidence - focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract
François Mach,Kausik K. Ray,Olov Wiklund,Olov Wiklund,Alberto Corsini,Alberico L. Catapano,Eric Bruckert,Guy De Backer,Robert A. Hegele,G. Kees Hovingh,Terry A. Jacobson,Ronald M. Krauss,Ulrich Laufs,Lawrence A. Leiter,Winfried März,Winfried März,Børge G. Nordestgaard,Børge G. Nordestgaard,Frederick J. Raal,Michael Roden,Raul D. Santos,Evan A. Stein,Erik S.G. Stroes,Paul D. Thompson,Lale Tokgozoglu,Georgirene D. Vladutiu,Baris Gencer,Jane K Stock,Henry N. Ginsberg,M. John Chapman +29 more
TL;DR: Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above, and the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects.
Journal ArticleDOI
Diagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance: Canadian Consensus Working Group Update (2016)
G.B. John Mancini,Steven K. Baker,Jean Bergeron,David Fitchett,Jiri Frohlich,Jacques Genest,Milan Gupta,Robert A. Hegele,Dominic S. Ng,Glen J. Pearson,Janet E. Pope,A. Yashar Tashakkor +11 more
TL;DR: More detailed analyses of specific but more unusual adverse effects ascribed to statins are updated including evidence regarding new-onset diabetes, cognitive dysfunction, cataracts, and the rare but important immune-mediated necrotizing myopathy.
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