A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia.
OBJECTIVE
The purpose of this study was to evaluate the efficacy and safety profile of ezetimibe/simvastatin(EZE/SIMVA) combination tablet, relative to ezetimibe (EZE) and simvastatin (SIMVA) monotherapy, in patients with primary hypercholesterolemia.


METHODS
This was a randomized, multicenter, double-blind, placebo-controlled, factorial design study After a 6- to 8-week washout period and 4-week, single-blind, placebo run in, hypercholesterolemic patients (low-density lipoprotein cholesterol [LDL-C], 145-250 mg/dL; triglycerides [TG], < or =350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: EZE/SIMVA 10/10, 10/20, 10/40, or 10/80 mg; SIMVA 10, 20, 40, or 80 mg; EZE 10 mg; or placebo. The primary efficacy analysis was mean percent change from baseline in LDL-C to study end point Secondary end points included percent changes in other lipid variables and C-reactive protein [CRP].


RESULTS
There were 1528 patients randomized to treatment (792 women, 736 men); mean (SD) age ranged from 54.9 (112) years to 56.4 (10.6) years across pooled treatment groups. The treatment groups were well balanced for baseline demographics. Pooled EZE/SIMVA was associated with greater reductions in LDL-C than pooled SIMVA or EZE alone (P < 0.001). Depending on dose, EZE/SIMVA was associated with reductions in LDL-C of -44.8% to -602%, non-high-density lipoprotein cholesterol of -40.5% to -55.7%, and TG of -22.5% to -30.7%; high-density lipoprotein cholesterol increased by 5.5% to 9.8%. EZE/SIMVA was associated with greater reductions in CRP and remnant-like particle-cholesterol than SIMVA alone (P < 0.001). More patients receiving EZE/SIMVA versus SIMVA achieved LDL-C concentrations <100 mg/dL (78.6% vs 45.9%; P < 0.001). EZE/SIMVA was generally well tolerated, with a safety profile similar to SIMVA monotherapy There were no significant differences between EZE/SIMVA and SIMVA in the incidence of consecutive liver transaminase levels > or =3 times the upper limit of normal (ULN) (1 .5% for EZE/SIMVA and 1.1% for SIMVA; P = NS) or creature kinase levels > or =10 times ULN (0.0% for EZE/SIMVA and 02% for SIMVA; P = NS).


CONCLUSIONS
The EZE/SIMVA tablet was a highly effective and well-tolerated LDL-C-lowering therapy in this study of patients with primary hypercholesterolemia.
Bays
Harold E
HE
Louisville Metabolic and Atherosclerosis Research Center, 3288 Illinois Avenue, Louisville, KY 40213, USA. HBaysMD@aol.com
Ose
Leiv
L
Fraser
Neil
N
Tribble
Diane L
DL
Quinto
Katherine
K
Reyes
Robert
R
Johnson-Levonas
Amy O
AO
Sapre
Aditi
A
Donahue
Steven R
SR
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000097:blood; D003627:Data Interpretation, Statistical; D004311:Double-Blind Method; D004338:Drug Combinations; D000069438:Ezetimibe; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013607:Tablets; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D001384:Azetidines; D008078:Cholesterol, LDL; D004338:Drug Combinations; D013607:Tablets; D014280:Triglycerides; D019821:Simvastatin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000069438:Ezetimibe