Long-term safety and tolerability profiles and lipid-modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment:: A multicenter, randomized, double-blind, placebo-controlled, 48-week extension study

被引:50
作者
Masana, L
Mata, P
Gagné, C
Sirah, W
Cho, M
Johnson-Levonas, AO
Meehan, A
Troxell, JK
Gumbiner, B
机构
[1] Univ Rovira & Virgili, E-43201 Reus, Spain
[2] Fdn Jimenez Diaz, E-28040 Madrid, Spain
[3] CHUQ, CHUL, Quebec City, PQ, Canada
[4] Merck Res Labs, Rahway, NJ USA
关键词
ezetimibe; simvastatin; hypercholesterolemia; coadministration; low-density lipoprotein cholesterol; safety;
D O I
10.1016/j.clinthera.2005.02.011
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background: Ezetimibe (EZE) is a cholesterol lowering drug that inhibits absorption of dietary and biliary cholesterol across the intestinal wall without affecting absorption of bile acids, fatty acids, fat-soluble vitamins, or triglycerides. It has a complementary mechanism of action to the statins, which inhibit cholesterol synthesis in the liver. Coadininistration of EZE and statins provides inhibition of 2 sources of cholesterol, leading to greater reductions in low-density lipoprotein cholesterol (LDL-C) than with either agent alone. Objectives: This study evaluated the long-term safety and tolerability profiles and lipid-modifying efficacy of treatment with EZE 10 mg/d plus simvastatin (SIMVA) 10, 20, 40, or 80 mg/d for 48 weeks in patients with primary hypercholesterolemia. Methods: This was an extension of a multicenter, double-blind, placebo (PBO)-controlled base study in which hypercholesterolemic patients were randomized to receive EZE 10 mg/d or PBO in addition to their current statin for 8 weeks. Patients who successfully completed the base study could enter the extension study if they were willing to switch from their current statin to an approximately equipotent dose of SIMVA for the 54-week study period. After a 6-week open-label SIMVA run-in phase, patients were rerandomized to receive EZE 10 mg/d or PBO in a 4:1 ratio, respectively, for 48 weeks. At each clinic visit, beginning at week 12, the dose of SIMVA was titrated upward until patients reached their National Cholesterol Education Program Adult Treatment Panel 11 LDL-C goal or the maximum SIMVA dose of 80 mg/d. Safety/tolerability and lipid efficacy parameters were assessed at 12-week intervals. Results: Of 433 patients entering the extension study, 355 were randomized to receive EZE and 78 were randomized to receive PBO. Baseline demographic characteristics and lipid levels were similar between treatment groups. Overall, coadministration of EZE + SIMVA was well tolerated. There were no clinically meaningful differences between the EZE and PBO groups with regard to the incidence of treatment related adverse events (AEs) (19% vs 17%, respectively), discontinuations due to AEs (7% vs 10%), serious AEs (12% vs 17%), consecutive elevations in liver function tests >= 3 times the upper limit of normal (ULN) (0.3% vs 0%), or elevations in creatine kinase >= 10 times the ULN (both, 0%). As in the base study, LDL-C levels were significantly lower with the addition of EZE to SIMVA compared with the addition of PBO (-24% vs 3%; P < 0.001). Conclusion: In these patients with primary hypercholesterolemia, EZE 10 mg/d added to ongoing SIMVA treatment for 48 weeks had a favorable safety and tolerability profile and was more efficacious than SIMVA monotherapy. Copyright (c) 2005 Excerpta Medica, Inc.
引用
收藏
页码:174 / 184
页数:11
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