Cerivastatin, genetic variants, and the risk of rhabdomyolysis

Abstract

Objective-The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response--rhabdomyolysis in a small proportion of users--points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis.Methods-The study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association (GWA) study to identify risk factors in other regions of the genome. 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies.Results-Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (p = 0.002), but not variants in CYP2C8 (p = 0.073) or the UGTs (p = 0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (OR: 1.89, 95% CI: 1.40 to 2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (p < 0.001). The GWA identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (p=1.74E-07). An additional copy of the minor allele of the This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

Clinical Perspective: Statins and the Liver—Harmful or Helpful?

“…Moreover, incidence estimates are unreliable when made from isolated postmarketing cases, and, coupled with the circumstantial evidence and confounding factors found in many of the patients described in recent case series, I would argue that the addition of such reports to the published literature should not change the practice patterns of physicians already prescribing statins, and nor should such reports deter or unduly influence those who hesitate to use statins because of their concern about statin-associated DILI. Statins are not without some risks, such as muscle injury and rarely rhabdomyolysis (which forced the withdrawal of cerivastatin in 2001, which in many cases occurred in patients receiving gemfibrozil in combination) [1,[99][100][101], and I agree with Bjornsson et al that even very rare side effects should never be disregarded [6]. However, with respect to hepatic injury, neither should such low frequency events be given undue emphasis [9,10].…”

Statin intolerance – an attempt at a unified definition. Position paper from an International Lipid Expert Panel

“…Statin toxicity became of general public interest in 2001, when cerivastatin was withdrawn from the market (52 deaths from rhabdomyolysis) although rhabdomyolysis was not observed in a meta-analysis of cerivastatin clinical trials [15,16]. Such side effects can impair the quality of life, adherence to treatment, and in extreme cases, may lead to death.…”

Genetics and Genomics for the Prevention and Treatment of Cardiovascular Disease: Update

“…What used to be regarded as idiosyncratic, unpredictable type B reactions, for instance, abacavir and the hypersensitivity syndrome, 217,218 flucloxacillin and drug-induced liver injury, 219,220 and statin-associated myopathy, 221,222 are now known to be strongly associated with specific genetic variants. At this stage, we now have randomized trial evidence that screening prevents hypersensitivity reactions to abacavir.…”

“…At this stage, we now have randomized trial evidence that screening prevents hypersensitivity reactions to abacavir. 223 Because of the large effect of study size for these drug-gene interactions, GWASs of severe adverse drug reactions have typically included 50 to 200 cases 217,219,220,222 rather than the tens or hundreds of thousands of subjects typically included in GWASs of phenotypes such as lipids and BP. 92,129 Lumiracoxib, a cyclooxygenase-2 inhibitor, for example, was never approved because of drug-induced liver injury.…”