Effects of Rosuvastatin Versus Atorvastatin, Alone or in Combination, on Lipoprotein (a)

Abstract Background: Elevated lipoprotein (a) [Lp(a)] is an independent risk factor for coronary artery disease (CAD). However, there is little evidence about the therapeutic efficacy of different lipid-lowering agents in reducing Lp(a). Objective: The primary objective of our study was to test the effect of different therapeutic treatment strategies on elevated Lp(a) levels, specifically to compare rosuvastatin versus atorvastatin alone or in combination with niacin or fibrates. The secondary objective was to analyze the occurrence of potential adverse effects. Methods: It was a prospective, single-center, interventional study. Patients with CAD, or high CAD risk, with increased Lp(a), >50 mg/dL, were included in the study. Lp(a), total cholesterol (C), triglycerides (TGs), high-density lipoprotein cholesterol and low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) A1, Apo B, and enzymes of myocyte and hepatic injury were comparatively analyzed between 4 lipid-lowering treatment strategies: rosuvastatin (R group) 40 mg, atorvastatin (A group) 80 mg, atorvastatin 40 mg add-on micronized fenofibrate (A+F group), and atorvastatin 40 mg add-on 1 g extended-release niacin (A+ERN group). Comparison was made for their lipid lowering therapeutic efficacy, primarily on Lp(a), and their safety profile. Results: A total of 87 patients, 61 ± 12 years old, were analyzed. The main risk factors were obesity (64.7%) and hypertension (64.6%). Men were more often smokers (odds ratio [OR] = 5.1) and had CAD (OR = 2.8), but lower total C (206.9 ± 32.9 vs 238.6 ± 47.9 mg/dL, P = 0.002) and LDL-C (136.5 ± 18.2 vs 160.9 ± 30.9 mg/dL, P = 0.000). Mean Lp(a) was 94.6 ± 39.6 mg/dL, without significant gender difference. There were 25 patients in the R group, 22 in the A group, and 20 each in the A+F and A+ERN groups. Significant reduction in all lipid fractions in all treatment groups was reported after 6 months. The average reduction of Lp(a) was 15.9 ± 21.0 mg/dL, with 18.2 ± 24.8 (P = 0.001) in the R group and similar values in the A+F and A+ERN groups (17.3 ± 10.4, P = 0.001, and 19.5 ± 10.9, P = 0.001, respectively), and the lowest in the A group (11.24 ± 22.91, P = 0.032). No adverse effects were observed in any of the treatment groups. Conclusions: When compared with atorvastatin, it seems that rosuvastatin can achieve a statistically more significant decrease of Lp(a). The efficacy of atorvastatin on the Lp(a) optimization can be increased by adding either fibrate or ERN. Given in recommended doses, all agents were well tolerated

Effects of single nucleotide polymorphisms and haplotypes of the SLCO1B1 gene on the pharmacokinetic profile of atorvastatin in healthy Macedonian volunteers

OATP1B1 is an influx transporter known to mediate the uptake of various endogenous compounds and xenobiotics. Several sequence variations have been discovered in the SLCO1B1 gene encoding OATP1B1. The aim of this study was to investigate the effects of SLCO1B1 polymorphisms on the pharmacokinet-ics of atorvastatin in healthy volunteers of Macedonian origin. Twenty three participants, genotyped for SLCO1B1 c.388A>G, c.521T>C, c.571T>C, c.597C>T, c.1086C>T, c.1463G>C and c.*439T>G polymorphisms using TaqMan allelic discrimination assay, ingested a single 80mg dose of atorvastatin. The plasma concentrations of atorvastatin were measured for 48h using Tandem Liquid Chromatography-Mass Spectrometry, LC-MS-MS, and the peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), elimination half-life (t1/2), constant rate of elimination (kel), mean residence time (MRT, expo), volume of distribution (Vd/kg), clearance (CL/kg), area under curve AUC0-48h and AUC0-∞ were determined.Our data confirmed that the SLCO1B1 gene is highly polymorphic, with a frequency of the c.521T>C single-nucleotide polymorphism (SNP) being the lowest (app. 15%) and of all other SNPs alleles above 40%. Exceptions were c.1463G>C and c.1086C>T SNPs for which variant alleles were not identified. The strongest correlation was observed between the c.521T>C and c.571T>C SNPs pair. The haplotype analysis revealed 10 different haplotypes, with *1J/*1K/*1L being the dominant, with a frequency of app. 40%. The haplotype *15/*16/*17, containing both variant alleles of the functionally most distinguished SNPs, c.388A>G and c.521T>C, occurred with a frequency of 13%. However, *15/*16/*17 homozygotes were not identified in the study group. In this study, no significant differences in the kel,t1/2,Cmax,Tmax,AUC0-48h, AUC0-∞, MRT expo, Vd and CL between the carriers of different c.388A>G, c.597C>T andc.*439T>G genotypes were observed. Subject with a variant allele C in the c.521T>C SNP, c.521CC genotype, had markedly higher values for Cmax and AUC0-48h, 140% and 67%, respectively, in comparison with the carriers of the c.521TT genotype. Also, the carriers of the variant allele C at c.571T>C SNP, c.571 CC genotype, had 55% and 43% lower mean Cmax and AUC0-48h in comparison with the carrier of c.571TT.These differences lacked statistical significance due to the size of the sample. In addition, no significant differences in the pharmacokinetic parameters of atorvastatin between the *15/*16/*17 heterozygotes and *15/*16/*17 non-carriers were observed. In conclusion, this extensive analysis of the effect of SLCO1B1 polymorphisms on the pharmacokinetic profile of atorvastatin showed that c.521T>C and c.571T>C SNPs may affect the inter-individual response to atorvastatin. Additional studies, with a large sample size, are needed to confirm this finding

Pharmacokinetic profile of atorvastatin in relation to SLCO1B1 C.521T>C and C.388A> variants in healthy volunteers

OATP1B1 is an influx transporter known to be implicated as important determinant of the intestinal absorption and hepatobiliary clearance of hydrophilic statins, such as atorvastatin. Several sequence variations have been discovered in the SLCO1B1 gene encoding OATP1B1, with some of them, such as c.388A>G (p.Asn130Asp) and c.521T>C (Val174Ala) associated with increased and reduced OATP1B1 activity, respectively. The aim of the study was to investigate the effects of these two SLCO1B1 SNPs on the pharmacokinetics of atorvastatin. Twenty three healthy Macedonian volunteers were genotyped for these two SNPs using TaqMan allelic discrimination assay. After ingestion of a single dose of 80 mg, the plasma concentrations of atorvastatin were measured for 48 h using LC-MS-MS and the Cmax, Tmax, t1/2, kel, MRT, Vd, CL, AUC0-48h and AUC0-~ were determined. Allele frequencies of the variants were in Hardy-Weinberg Equilibrium, with 39 and 15% for c.388A>G and c.521T>C, respectively. Low correlation between this SNP pair (R2=0.137; D’=0.700) was observed. No significant differences in the kel, t1/2, Cmax, Tmax, AUC0-48h, AUC0-~, MRT, Vd and CL between the carriers of different c.388A>G genotypes were observed. Subject with a c.521CC genotype had markedly higher values for Cmax and AUC0-48h, 140 and 67% respectively, in comparison with the carriers of the c.521TT genotype. These differences lacked statistical significance due to the size of the sample. In addition, the effects of SLCO1B1 diplotypes on pharmacokinetic parameters were investigated comparing the effects of *15 non-carriers (n=17) and *15 heterozygotes (n=6), as *15 homozygotes were not identified in the study. The dominant effect of the c.521T>C SNP was confirmed. Marginal statistical differences were observed in Cmax, AUC0-48h, AUC0-~ and CL, with Cmax and AUC0-~ 45% (p=0.062) and 38% (n=0.09) higher, and CL 30% (p=0.07) lower in *15 heterozygotes/carriers of c.521C allele. Additional studies, with a large sample size are needed to confirm this finding

Frequencies of single-nucleotide polymorphisms and haplotypes of the SLCO1B1 gene in selected populations of the Western Balkans

As a membrane influx transporter, organic anion-transporting polypeptide 1B1 regulates the cellular uptake of a number of endogenous compounds and drugs. The aim of this study was to characterize the diversity of the SLCO1B1 gene encoding this transporter in two ethnic groups populating the Western Balkans. The distribution of SCLO1B1 alleles was determined at seven variant sites (c.388A>G, c.521T>C, c.571T>C, c.597C>T, c.1086C>T, c.1463G>C and c.*439T>G) in 266 Macedonians and 94 Albanians using the TaqMan allelic discrimination assay. No significant difference in the frequencies of the single nucleotide polymorphisms (SNPs) was observed between these populations. The frequency of the c.521T>C SNP was the lowest (C and c.1086C>T SNPs were not identified in either ethnic group. The haplotype analysis revealed 20 and 21 different haplotypes in the Macedonian and Albanian population, respectively. The most common haplotype in both ethnic groups, *1J/*1K/*1L, had a frequency of 39.0% and 26.6%, respectively. In both populations, the variant alleles of the functionally significant c.521T>C and c.388A>G SNPs existed in one major haplotype (*15/*16/*17), with a frequency of 8.6 and 2.4% in the Macedonian and Albanian subjects, respectively. In conclusion, sequence variations of the SLCO1B1 gene in the studied populations occur at high frequencies, which are similar to that of the Caucasian population. Further studies are needed to evaluate the clinical significance of these SNPs and/or the major SLCO1B1 haplotypes they form for a large number of substrates and for susceptibility to certain diseases