Lipoprotein and apolipoprotein ratios in the VYTAL trial of ezetimibe/simvastatin compared with atorvastatin in type 2 diabetes.
ABSTRACT Type 2 diabetes mellitus (T2DM) is associated with a high risk for coronary heart disease (CHD). A variety of lipoprotein and apolipoprotein (Apo) ratios have been proposed that may reflect the balance of cholesterol delivery and removal at the arterial wall and provide an assessment of CHD risk that is supplemental to low-density lipoprotein cholesterol (LDL-C), the primary guide for cholesterol-lowering therapy in patients at risk.
To examine changes in lipoprotein and apolipoprotein ratios in the VYTAL trial of hypercholesterolemic patients with T2DM.
Changes in the ratios LDL-C/high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC)/HDL-C, non-HDL-C/HDL-C, and ApoB/ApoA-I were assessed in this randomized, double-blind, parallel-group study that enrolled T2DM patients with LDL-C ≥100 mg/dL for 6-week treatments with either the usual daily starting doses of atorvastatin (ATORVA) 10 or 20 mg or ezetimibe/simvastatin (EZE/SIMVA) 10/20 mg, or the next highest doses (ATORVA 40 mg, EZE/SIMVA 10/40 mg). Changes in lipoprotein and apolipoprotein ratios, prespecified exploratory endpoints, were analyzed using analysis of variance.
Efficacy results were based on 1198 patients with sufficient data among 1229 randomized patients. Baseline lipoproteins, apolipoproteins, and ratios were comparable among treatment groups. EZE/SIMVA produced significantly greater reductions compared with ATORVA in each lipoprotein or apolipoprotein ratio at each dose comparison (P < 0.001). For example, reductions from baseline in TC/HDL-C were ATORVA 10 mg, -30.2%; ATORVA 20 mg -34.9%; EZE/SIMVA 10/20 mg, -41.6%; ATORVA 40 mg, -37.9%; and EZE/SIMVA 10/40 mg, -43.5%. Tolerability of the two treatments was similar.
For the doses assessed, EZE/SIMVA was more effective compared with ATORVA in lowering the lipoprotein and apolipoprotein ratios that might be considered secondary measures of CHD risk.
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ABSTRACT: BACKGROUND AND OBJECTIVES: Ezetimibe/simvastatin combination tablet has been approved for the treatment of high low-density lipoprotein cholesterol (LDL-C) levels in patients with primary hypercholesterolaemia or mixed hypercholesterolaemia as adjunctive therapy to diet, when diet alone is insufficient in lowering cholesterol. The aims of this study were to assess the pharmacokinetics and safety of an ezetimibe/simvastatin combination tablet after oral single-dose administration in healthy Chinese subjects including sex-related differences in pharmacokinetics. METHODS: This was an open-label, single-dose study. Twelve healthy subjects (six males and six females) received a single dose of an ezetimibe/simvastatin combination tablet (ezetimibe 10 mg and simvastatin 40 mg). The pharmacokinetic parameters for ezetimibe and simvastatin were assessed by determining total ezetimibe, free ezetimibe, simvastatin and simvastatin acid concentrations using a validated liquid chromatography-tandem mass spectrometry method. Safety was evaluated by monitoring adverse events, laboratory assays, vital signs, physical examinations and 12-lead electrocardiograms. RESULTS: The pharmacokinetic parameters (mean ± SD) for total ezetimibe and free ezetimibe following a single dose were: maximum plasma drug concentration (C(max)) 81.56 ± 26.62 and 9.40 ± 6.17 ng/mL; time to reach C(max) (t(max)) 0.93 ± 0.30 and 1.25 ± 1.27 h; elimination half-life (t(½)) 24.32 ± 13.27 and 18.90 ± 9.66 h, and mean area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(last)) 579.06 ± 241.45 and 126.01 ± 69.01 ng·h/mL, respectively. The pharmacokinetic parameters (mean ± SD) for simvastatin and simvastatin acid following a single dose were: C(max) 11.92 ± 5.50 and 3.37 ± 1.78 ng/mL, t(max) 0.98 ± 0.28 and 3.73 ± 1.68 h, t(½) 4.19 ± 1.81 and 7.65 ± 7.96 h, and mean AUC(last) 33.63 ± 20.41 and 32.50 ± 18.79 ng·h/mL. Higher AUC(last) and AUC from time zero to infinity (AUC(∞)), and lower apparent total body clearance of drug from plasma after oral administration (CL/F) for total ezetimibe and free ezetimibe were observed in female subjects compared with those in male subjects. There were no differences between the pharmacokinetic parameters of simvastatin and simvastatin acid for female and male subjects in the study. CONCLUSION: Ezetimibe/simvastatin combination tablet has a generally favourable safety and tolerability profile in healthy Chinese subjects. A statistically significant difference with regard to sex in the pharmacokinetics of ezetimibe was observed. Sex had no effect on the pharmacokinetics of simvastatin and simvastatin acid.Clinical Drug Investigation 10/2012; · 1.92 Impact Factor