Function-impairing polymorphisms of the hepatic uptake transporter SLCO1B1 modify the therapeutic efficacy of statins in a population-based cohort

Abstract

Background The efficacy of statins, which are used commonly in primary and secondary prevention of cardiovascular diseases, shows a wide range of interindividual variability. Genetic variants of OATP1B1, a hepatic uptake transporter, can modify access of statins to its therapeutic target, thereby potentially altering drug efficacy. We studied the impact of genetic variants of OATP1B1 on the lipid-lowering efficacy of statins in a population-based setting. Materials and methodsThe basis of the analysis was the Study of Health in Pomerania, a cohort of 2732 men and women aged 20-81 years. Included in the statistical analysis to evaluate the impact of OATP1B1 on therapeutic efficacy of statins were 214 individuals diagnosed with dyslipidaemia during initial recruitment and receiving statins during the 5-year follow-up.Results Analysing the impact of the OATP1B1 genotype, we observed a trend for lower statin-induced total cholesterol reduction in carriers of the SLCO1B1 512C variant. Restricting the analysis to patients receiving simvastatin, pravastatin, lovastatin and fluvastatin indicated a statistically significant association of the OATP1B1 genotype on lipid parameters at the 5-year follow-up. No such effect was observed for atorvastatin. Calculation of achievement of treatment goals according to the NCEP-ATPIII guidelines showed a lower rate of successful treatment when harbouring the mutant allele for patients taking simvastatin (46.7 vs. 73.9%). A similar trend was observed for pravastatin (34.4 vs. 70.4%).Conclusion Genetic variants of OATP1B1 leading to impaired hepatic uptake of statins translated into reduced drug efficacy in a population-based cohort.

A genetic risk score is significantly associated with statin therapy response in the elderly population

“…ABCC2, carrying the variant rs2002042 that was identified by RF analysis as well, belongs to a family of transporters known to interact with lipophilic statins (23). Interestingly, in our context of elderly individuals, SLCO1B1 SNPs did not show a major role on LDL-C response to statins as shown in previous studies (25). Interestingly, in our context of elderly individuals, SLCO1B1 SNPs did not show a major role on LDL-C response to statins as shown in previous studies (25).…”

The Influences of SLCO1B1 and ABCB1 Genotypes on the Pharmacokinetics of Simvastatin, in Relation to CYP3A4 Inhibition

“…We estimate that patients with both risk factors are likely to have a much higher chance of developing myopathy. In addition, it is worth noting that both the FDA and the UK Medicines and Healthcare products Regulatory Agency propose a 50% lower dose of simvastatin for patients who coadminister amlodipine -it is unknown how this practice will influence the clinical outcomes of simvastatin treatment, particularly in patients carrying the SLCO1B1 c.521T>C variant, who are less responsive to simvastatin [33,34]. In conclusion, SLCO1B1 geno typing may be critical for simvastatin users who unavoidably take CYP3A4 inhibitors such as amlodipine, in order to lower the risk of adverse effects and impaired drug efficacy.…”

Differences in Genetic Variants in Lopinavir Disposition Among Hiv-Infected Bantu Africans

“…OATP1B1 (coded for by SLCO1B1 gene) is involved in the hepatic uptake of many substrates and plays an important role in transporting LPV [11][12][13], thus, genetic variation in SLCO1B1 is likely to affect LPV plasma variability. SLCO1B1 c.521T>C was monomorphic in this African cohort yet its effects on disposition of statins has been extensively reported among Caucasians, African-Americans [28][29][30][31] and Asians [32]. We cannot rule out a role for SLCO1B1 genetic variation in LPV plasma variability, but, can deduce that there could be other African-specific variants that have not yet been reported that need to be investigated.…”

“…We did not find significant genetic predictors of LPV plasma concentration. Several studies among Caucasians [18,[26][27][28][29][30] have reported an association of CYP3A4*22 with increased drug plasma concentrations for drugs that are substrates of CYP3A4, however, in this cohort, the allele was absent (0%) yet LPV plasma concentration variability was still huge (>1800-fold). This shows that there could still be some variants in CYP3A4 among African populations that need to be discovered and reported.…”