Impact of Genetic Variation in the SLCO1B1 Gene on Statin Efficacy in Low-Density Lipoprotein Cholesterol-Lowering Therapy

KEYWORDS::

• hypercholesterolemia
• hypolipidemic response
• pharmacogenetic
• statin-induced myopathy

Elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) constitute a major cause of premature coronary heart disease. Observational studies indicate a continuous and positive association between the risk of coronary heart disease and LDL-C concentrations. As a consequence, statin therapy, which acts by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the de novo synthesis of cholesterol, has proven to be highly efficacious, not only in lowering circulating concentrations of atherogenic LDLs, but also in reducing cardiovascular (CV) morbi–mortality. Indeed, since the pioneering Scandinavian Simvastatin Survival Study (4S) trial [1], which demonstrated for the first time that statins reduce mortality in patients at high cardiovascular risk, several large prospective, placebo-controlled, randomized clinical trials of HMG-CoA reductase inhibitors have been completed. Very recently, the Cholesterol Treatment Trialists‘ (CTT) Collaboration reported a meta-analysis [2] based on 26 randomized clinical trials involving more than 170 000 participants. This analysis revealed that each 1.0 mmol/l reduction of LDL-C directly results in the reduction in the annual rate of major vascular events (coronary death or nonfatal myocardial infarction, coronary revascularisation and ischemic stroke) by just over one fifth. The investigators notably included five trials (Pravastatin or Atorvastatin Evaluation and Infection Therapy– Thrombolysis in Myocardial Infarction 22 [PROVE IT-TIMI 22], Treating to New Targets [TNT], Aggrastat to Zocor [A to Z], Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL], Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine [SEARCH]) designed to compare more-intensive lipid lowering therapy with less intensive treatments, thereby demonstrating that reductions in CV risk per mmol/l reduction in LDL-C were similar, irrespective of the baseline concentration of LDL-C, even in patients with baseline LDL-C less than 2 mmol/l. Taken together, these data imply that lowering LDL-C by 2–3 mmol/l with more intensive statin therapy would further reduce risk by approximately 40–50%. However, by proving the benefit of the ‘lower is better‘ approach, such evidence-based medicine inevitably leads to the use of higher statin doses and thus favors elevation in adverse effects. Indeed, the recently published results of SEARCH [3] documented an absolute excess of myopathy in about four patients per 1000 per year during the first year of treatment with the highest dose regimen (i.e., 80 mg simvastatin); such rates should be compared with an estimated incidence of 1.6 cases of myopathy per 100 000 person-years for all statins combined [4]. Although the exact mechanisms implicated in the development of myopathy are still unclear, it is widely accepted that the development of adverse reactions is intimately related to statin plasma concentration and the area under the plasma concentration–time curve. There is a considerable interest therefore in maximizing the reduction of LDL-C with statin therapy with minimal risk of adverse effects and/or predicting which patients are at high risk of adverse drug reactions.

For these reasons, the management of dyslipidemia with statins may take advantage of a personalized pharmacological approach based on the results of efficacy-oriented and toxicity-oriented pharmacogenetic studies. In this regard, it was initially believed that genes involved in lipid metabolism would constitute the key determinants of statin response [5]. However, as the liver constitutes not only the target organ of HMG-CoA reductase inhibitors, but also the key site for their metabolism and clearance, interest has focused on the potential of genetic variations in hepatic transporters to influence both the pharmacokinetics and pharmacodynamics of this class of drug. Among these transporters, the organic anion-transporting polypeptide member 1B1 (OATP1B1, also known as OATP-C, liver specific transporter-1 or OATP2), which is encoded by the Solute Carrier Organic Anion Transporter Family, member 1B1 (SLCO1B1), is implicated in statin pharmacogenetics. Interestingly, there is a paucity of data on OATP1B3 (encoded by SLCO1B3, also expressed exclusively in the liver), and OATP2B1 (encoded by SLCO2B1, expressed ubiquitously) [6]. OATP1B1, which is expressed at the basolateral membrane of the human hepatocyte, is responsible for the hepatocellular uptake of a spectrum of endogenous and foreign substances, which include statins [7,8]. Such uptake determines both intrahepatocyte and residual circulating statin concentrations and potentially constitutes one of the rate-limiting steps in the action of this class of drug. In 2001, Tirona et al. reported 14 nonsynonymous SNPs representing 16 distinct haplotypes, named SLCO1B1*1b to SLCO1B1*14 (reference haplotype: SLCO1B1*1a) [9]. Since then, three new haplotypes, *15 to *17, have been described [6].

Numerous in vitro and in vivo pharmacokinetic studies have been performed exploring the potential impact of these SLCO1B1 variants (for review see [10]). The most compelling evidence, derived from in vivo studies, indicates that the *5 and *15 haplotypes may be associated with a reduced cellular uptake of statins and consequently an increased plasma area under the plasma concentration–time curve. In addition, it has been suggested that the *1b allele may confer an elevated transmembrane transport activity in comparison with the reference haplotype *1a. However, it is more likely that the intensity of these effects is largely dependent on the type of statin and its chemical form, notably the lactone or acid. Pharmacodynamic studies have also been performed in order to investigate the effects of these haplotypes on the lipid-lowering efficacy of statins. Some studies, notably those on a limited number of patients, have shown that the *5 and/or *15 alleles are associated with attenuated LDL-C lowering [10], whereas one study demonstrated an enhanced response to statin in patients exhibiting a common haplotype in Caucasians (SLCO1B1*14); this allele corresponds to a frequent variant associated with the *1b haplotype [11]. These results, even if they are consistent with in vivo pharmacokinetic studies, were not reproduced in larger cohorts, probably as a consequence of substrate-dependent responses. Very interestingly, Takane et al. pinpointed the importance of determining the time point when on-treatment cholesterol data were obtained in these pharmacodynamic studies [12]. Indeed they reported a significantly attenuated LDL-C lowering in carriers of the *15 allele after 8 weeks of treatment. However, this association was lost when the analysis was repeated after 1 year. They suggested therefore that SLCO1B1 haplotypes may be predictive of a slower rather than a prolonged attenuated response to statin therapy.

In summary, a large body of evidence based on pharmacokinetic and pharmacodynamic results suggests that SLCO1B1 genotype contributes to interindividual variability of the LDL-C lowering response to statin therapy. However, efficacy-oriented pharmacogenetic approaches restricted to these genetic markers are unlikely to be clinically compelling, notably owing to the lack of reproducibility for all statins and because of the low proportion of variability in response that they can explain. One may suggest that such SLCO1B1 genotypes could be used as part of a pharmacogenetic panel designed to address the question as to whether a poor response to statin therapy might be attributed to faulty compliance or to genetically determined resistance.

In addition to the efficacy-oriented pharmacogenetic approach, it has been suggested that SLCO1B1 genotyping may be of greater clinical significance in a toxicity-oriented pharmacogenetic approach. Indeed, as mentioned earlier, some pharmacokinetic studies demonstrate that SLCO1B1 variants affect OATP1B1 transport function, resulting in an increase in residual plasma statin concentration and a possible elevated risk of adverse muscular effects. In support of this hypothesis, the investigators in the SEARCH trial reported that an OATP1B1 variant present in both *5 and *15 haplotypes was significantly associated with the risk of simvastatin-induced myopathy [13]. It is of great interest to note that this finding resulted from a genome-wide approach with more than 300,000 SNPs tested for association between statin treatment and risk of myopathy. In this study, roughly 60% of the myopathy cases could be attributed to the SLCO1B1 variant. Nevertheless, the cumulative risk for the development of myopathy was modest with a maximum of 18% for the rare subjects (2.1% of the population) being homozygous for this variant, which means that less than one fifth of the patients carrying the genotype at high risk were subject to myopathy. These findings were confirmed by another group with simvastatin, but not with pravastatin [14,15]. It is clear that the clinical significance of these findings is greater than that what was previously described for the efficacy-oriented pharmacogenetic approach. However, the possible substrate-dependent prediction of the risk of statin-induced myopathy, combined with the relatively low cumulative risk associated with this prediction, will reduce the cost–effectiveness of such a toxicity-oriented pharmacogenetic approach.

In conclusion, the role of OATP1B1 in the variability of response to statin therapy is undoubtedly well documented; nonetheless, SLCO1B1 genotyping is not sufficiently predictive of either toxicity or efficacy to be used alone.

Financial & competing interests disclosure

John Chapman discloses research funding and consultancies with Merck and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

John Chapman discloses research funding and consultancies with Merck and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.