Lipid-lowering response of the HMG-CoA reductase inhibitor fluvastatin is influenced by polymorphisms in the low-density lipoprotein receptor gene in Brazilian patients with primary hypercholesterolemia

Abstract

Although the efficacy of fluvastatin (HMG-CoA reductase inhibitor) in the treatment of primary hypercholesterolemia is well documented, a wide interindividual variation treatment response has been observed. We have studied the possible role of the AvaII (exon 13), HincII (exon 12), and PvuII (intron 15) polymorphisms at the low-density lipoprotein receptor (LDLR) gene on lipid-lowering response in 55 patients (36 to 70 years old) with primary hypercholesterolemia treated with fluvastatin for 16 weeks. LDLR genotypes were determined by PCR-RFLP. The results indicate that the AvaII and PvuII polymorphisms influence the cholesterol-lowering response of the HMG-CoA reductase inhibitor Fluvastatin. Patients carrying A+A+ (AvaII) or P1P1 (PvuII) homozygous genotypes presented lower reduction in total cholesterol, LDL-C and apolipoprotein B levels after 16 weeks of treatment with fluvastatin, when compared to other genotypes (P<0.05). Our data also support the previous assumption that the AvaII, HincII, and PvuII polymorphisms of the LDLR gene are associated with variation of serum cholesterol levels. Therefore, the identification of the LDLR genetic profile may provide better prediction of a patient's clinical response to fluvastatin.

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia

“…68 Greater Tc-and LDL-lowering effects in response to fluvastatin therapy was demonstrated in LDLR AvaII and PvuII genotypes (8 mmol/L greater Tc-level lowering, p=0.043, and 4 mmol/l greater LDL-level lowering, p=0.023, with absence of these restriction sites). 70 The LDLR HincII genotype was not associated with variable lipid response to lovastatin therapy at this time. 70 Fluvastatin Pharmacogenetics: Safety A 79-97% increase in the AUC of fluvastatin was identified in individuals with the ABCG2 rs2231142 variant compared with variant carriers (p=0.015) or homozygous wild-type alleles (p=0.009), but the effect of the variant on the lipid-lowering efficacy of fluvastatin has yet to be established.…”

“…70 The LDLR HincII genotype was not associated with variable lipid response to lovastatin therapy at this time. 70 Fluvastatin Pharmacogenetics: Safety A 79-97% increase in the AUC of fluvastatin was identified in individuals with the ABCG2 rs2231142 variant compared with variant carriers (p=0.015) or homozygous wild-type alleles (p=0.009), but the effect of the variant on the lipid-lowering efficacy of fluvastatin has yet to be established. 67 Fluvastatin is readily absorbed from the small intestine but undergoes extensive first-pass metabolism to inactive metabolites by CYP2C9; to a lesser extent, CYP3A4, CYP2C8, and CYP2D6 are also involved in fluvastatin metabolism.…”

“…68 The ABCB1 rs1922242 variant was associated with greater efficacy in lowering LDL, and variants in LDLR also showed better response to fluvastatin. 66,70 We found no studies that specifically connected patient outcomes with pharmacogenetic variants in the context of fluvastatin therapy, but the ACE deletion was associated with greater coronary artery disease regression (24% with deletion vs 3% without deletion) and slowed progression (14% with deletion vs 33% without deletion) in patients taking fluvastatin, as measured by changes in the mean lumen diameter. 68 Greater Tc-and LDL-lowering effects in response to fluvastatin therapy was demonstrated in LDLR AvaII and PvuII genotypes (8 mmol/L greater Tc-level lowering, p=0.043, and 4 mmol/l greater LDL-level lowering, p=0.023, with absence of these restriction sites).…”

Characterization of LDLR rs5925 and PCSK9 rs505151 genetic variants frequencies in healthy subjects from northern Chile: Influence on plasma lipid levels

“…[7][8][9] Besides, this genetic variant was strongly associated with differences on plasma lipid levels in subjects with high risk of CVD and lower response to fluvastatin treatment. 9,10 On the other hand, this LDLR variant was associated with low LDL-C in Italian individuals and was not associated with change in lipid profile in European subjects from Germany, the Netherlands, and Denmark. 11,12 Moreover, no association was found between…”

Efecto de variantes de los genes ABCB1 y CYP3A4 sobre la respuesta terapéutica a atorvastatina en individuos chilenos hipercolesterolémicos

“…A la fecha, se han investigado más de 40 genes que afectan la respuesta a estatinas 10 , relacionados tanto con la farmacocinética (enzimas de metabolización y proteínas de transporte) como con la farmacodinámica del medicamento (receptores y vías de transducción de señal) 11 . Estas variaciones incluyen a genes que actúan en la absorción intestinal de colesterol como la apolipoproteína E (APOE), transportador de ATP (ABC); la producción de colesterol, como la HMG-CoA reductasa; el metabolismo de las lipoproteínas como la apolipoproteína B y el receptor de LDL, como además, de aquellos que actúan en la vía de la citocromo P450 [12][13][14][15] . Las estatinas son metabolizadas por vía hepática, principalmente por la familia de la citocromo P450.…”