SLCO1B1 genetic variants, long-term low-density lipoprotein cholesterol levels and clinical events in patients following cardiac catheterization

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From: Pharmacogenomics(Vol. 16, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 5,798 words
Lexile Measure: 1800L

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Author(s): Josephine H Li aff1 , Sunil Suchindran aff1 , Svati H Shah aff2 aff3 , William E Kraus aff2 aff3 , Geoffrey S Ginsburg aff1 aff3 , Deepak Voora [*] aff1 aff3

Keywords:

cardiovascular events; low-density lipoprotein cholesterol; myocardial infarction; pharmacogenetics; rs4149056; rs2306283; SLCO1B1 ; statin

Statins are widely prescribed medications that prevent major coronary artery disease (CAD) events such as myocardial infarction (MI) primarily through the reduction of low-density lipoprotein cholesterol (LDL-c) [1 ]. Despite the well-established benefits of statins, current management remains suboptimal with a substantial portion of patients failing to achieve significant LDL-c lowering in clinical practice [2,3 ]. A major barrier to long-term LDL-c lowering is statin adherence [ 4 ]. In patients with CAD, up to 50% were nonadherent to statins after 1 year [ 5,6 ]. One main reason for nonadherence is the development of statin-induced musculoskeletal side effects [7 ]. In randomized clinical trials, the incidence of statin-induced myopathy has been reported as 1-5% [8,9 ] whereas observational studies suggest the frequency of statin myopathy to be 9-20% [10-13 ]. The reason for this discrepancy is not fully explained but can be attributed, in part, to more stringent screening in clinical trials that exclude patients with renal/hepatic insufficiency, history of prior intolerance or musculoskeletal complaints, as well as the use of 'run-in' phases. Furthermore, randomized control trials often only focused on rhabdomyolysis, the most severe form of myopathy or large elevations in creatine kinase, rather than other common side effects, which include myalgia with or without CK elevations [9,13,14 ].

Genetic variation in SLCO1B1 has been well described; the two most common functional variants in SLCO1B1 are rs4149056 and rs2306283. The C allele at rs4149056 (referred to as the *5 variant) causes a V174A substitution in the hepatic transporter protein OATP1B1 and is a risk factor for statin-induced side effects and premature drug discontinuation [15-17 ]. The *5 variant interferes with localization of the hepatic drug transporter to the plasma membrane, resulting in elevated systemic concentration of statins [ 18,19 ]. The effect of the *5 variant on statin clearance appears to be statin-specific, where simvastatin and atorvastatin are most affected, followed by fluvastatin, pravastatin and rosuvastatin [20 ]. The risk of myopathy conferred by *5 mirrors this pharmacokinetic data, with the greatest effects on simvastatin and atorvastatin and the least on pravastatin and rosuvastatin [ 16,21,22 ]. By interfering with statin transport into the hepatocyte, the *5 variant is associated with mild reductions in LDL-c lowering (1-3%) in short-term statin exposure studies ([less than or equal to]1 year) [ 15,16,22-26 ]. In contrast to the *5 variant, which reduces OATP1B1 function, the G allele at rs2306283 (referred to as the *1B variant) causes an N130D substitution that may increase OATP1B1 function [ 27 ]. As a consequence, the G allele reduces systemic statin concentrations [ 28 ] as well as the risk for statin-induced side effects [29 ] but does not result in differences in LDL-c lowering [26 ].

Because genetic variants in SLCO1B1 are associated with intermediate outcomes (i.e., hepatic exposure, systemic concentrations, side effects,...

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Gale Document Number: GALE|A411315285