Predictive Value Of Plasma Statins Exposure On Clinical Outcomes And Impact Of ADME Genetic Variation

Statin,as the first-line lipid-lowering drug,is widely used in primary and secondary prevention of coronary artery disease(CAD).It is effective in improving long-term survival However,the choice of intensity for initiating statins remains unclear and hotly debated,and recommendations varied among guidelines.There is no direct safety evidence on high intensity statins treatment in Chinese patients.Plasma exposure of statins and metabolites are the keypoint to evaluate efficacy and toxicity.Therefore,the present study sought to evaluate the association between systemic plasma exposure of atorvastatin and clinical outcomes in Chinese patients with CAD,and validate the association in patients undergoing rosuvastatin therapy.Multi-stage genome analyses were conducted to systematically identify new functional ADME genetic variants associated with atorvastatin metabolism.Firstly,we quantitatively analyzed the systemic exposure of atorvastatin,rosuvastatin and metabolites,and investigated the association between plasma levels and the occurrence of major adverse cardiovascular events(MACE),re-ischemia events and death in 2448 patients,and contrast-induced acute kidney injury(CI-AKI)in 1219 patients,respectively.Results demonstrated that moderate statin exposure could achieve equal or better efficacy in terms of composite cardiovascular events compared to low plasma exposure,while high exposure of statins and metabolites might increase the risk of death and CI-AKI.Secondly,a genome analysis was performed to identify SNPs associated with atorvastatin exposure in 857 patients with CAD,and particularly focusing on the genes involved in ADME.10 candidate SNPs associated with atorvastatin metabolism were selected,including UGT1A1*6(P=1.17E-06,FDR=1.08E-03).To validate the predictable effects of candidate SNPs on atorvastatin metabolism,another analysis of 228 patients with CAD was conducted.The results comfirmed that UGT1A1*6 gene polymorphism(P=5.40E-05,MAF=0.1421)may affect the metabolism of atorvastatin in patients with CAD.We further evaluated the impact of candidate SNPs genotyping on the risk of clinical endpoints in 1085 patients.The results showed that UGT1A1*6 and UGT1A1*60 were both significantly associated with atorvastatin metabolism and risk of clinical outcomes.Finally,we analyzed whether these new variants have potential impacts on the activation of atorvastatin in 55 human liver microsomes extracted from noncancerous liver tissues.The incubation condition of atorvastatin in human liver microsome was well established and optimized.The formation of metabolites in individual liver microsome was analyzed,and then compared among different genotypes of candidate SNPs.The results showed that CYP3A,UGT1A1 and UGT1A9 enzyme activity were associated with the formation rates of metabolites.UGT1A1*6 was found to be significantly associated with formation rates of 2-OH atorvastatin(P=0.0344).In conclusion,this study suggests for the first time that high plasma exposure of statins and metabolites may significantly increase the risk of death and CI-AKI,while moderate exposure could achieve equal or better efficacy in terms of composite cardiovascular events;and systematically identified UGT1A1*6 gene polymorphism associated with atorvastatin metabolism.Plasma concentration measurement and genotyping detection might provide certain reference significance for clinical personalized medicine to optimize therapy.