Background Dyslipidemia is the primary risk factor for cardiovascular disease, and statins
have been effective in controlling lipid levels. Sex differences in the
pharmacokinetics and pharmacodynamics of statins contribute to interindividual
variations in drug efficacy and toxicity. Objective To evaluate the presence of sexual dimorphism in the efficacy and safety of
simvastatin/atorvastatin treatment. Methods Lipid levels of 495 patients (331 women and 164 men) were measured at baseline
and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the
efficacy and safety profiles of both drugs. Results Women had higher baseline levels of total cholesterol (TC), low-density
lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)
compared with men (p < 0.0001). After treatment, women exhibited a greater
decrease in plasma TC and LDL-C levels compared with men. After adjustment for
covariates, baseline levels of TC and LDL-C influenced more than 30% of the
efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia
[with or without changes in creatine phosphokinase (CPK) levels] occurred more
frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal
liver function was more frequent in in men (17.9%; p = 0.017). Conclusions Our results show that baseline TC and LDL-C levels are the main predictors of
simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they
suggest the presence of sexual dimorphism in the safety of
simvastatin/atorvastatin. The effect of sex differences on receptors, transporter
proteins, and gene expression pathways needs to be better evaluated and
characterized to confirm these observations.
Lipid-lowering therapy has shown a high degree of variability in clinical response and there is evidence that the variability in drug response between individuals is due to genetic factors. Thirteen single nucleotide polymorphisms (SNPs) within the ESR1 gene were evaluated with basal lipid and lipoprotein levels, as well as response to lipid-lowering therapy, in 495 hypercholesterolemic individuals of European descent receiving simvastatin or atorvastatin. Significant associations were detected between rs4870061 (P=0.040, corrected P-value (PC)=0.440), rs1801132 (P=0.002, PC=0.022) and the SNP rs3020314 (P=0.013, PC=0.143) with triglyceride (TG) baseline levels. The rs4870061 was also associated with high-density lipoprotein cholesterol (HDL-C) baseline levels (P=0.045, PC=0.495). Regarding statin efficacy, rs2234693 C/C was associated with greater HDL-C increase (P=0.037; PC=0.407) and rs3798577 T allele was associated with greater total cholesterol (TC) reduction (P=0.019; PC=0.209) and greater TG reduction (P=0.026; PC=0.286). These associations suggest that ESR1 polymorphisms are in part responsible for the TC, HDL-C and TG variation levels and this effect may be sex-specific.
The data showed the presence of an association between the UGT1A1*28/*28 and SULT1A1*2/*2 and T-chol and LDL-C levels in women with different hormonal status. No previous studies investigated the association of the polymorphisms examined in this study with lipoprotein levels in women separately by hormonal status.
Our findings suggest that, in HT+ postmenopausal women, the rs2813544 polymorphism may influence LDL-C levels and, as previously described, ESR2 rs1256049 is associated with T-chol and LDL-C. No previous study has investigated the association of this SNP set with lipoprotein levels in women while taking into account the hormonal status of the patients.
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