Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin.
BACKGROUND
The level and duration of exposure to circulating low-density lipoprotein-cholesterol (LDL-C) are major contributors to coronary atherosclerosis. Therefore, optimal prevention will require long-term LDL-C reduction, making it important to select the most effective agent for each individual.


OBJECTIVE
We tested the hypothesis that individuals with high fractional absorption of cholesterol respond better to the cholesterol absorption inhibitor ezetimibe than to simvastatin, whereas low absorbers, who have elevated rates of cholesterol synthesis, respond better to simvastatin.


METHODS
A randomized, double-blind, placebo-controlled, crossover trial was performed in 215 African- and European-American men.


METHODS
Participants were randomized to placebo, ezetimibe (10 mg/d), simvastatin (10 mg/d), and both drugs for 6 wk each.


RESULTS
Plasma levels of LDL-C, surrogate markers for cholesterol absorption (campesterol) and synthesis (lathosterol), and proprotein convertase subtilisin-like kexin type 9 were measured at baseline and after treatment.


RESULTS
LDL-C levels were reduced by 19% (ezetimibe), 25% (simvastatin), and 41% (ezetimibe+simvastatin) from a baseline of 146 +/- 20 mg/dl; results were similar between ethnic groups. Reduction in LDL-C correlated poorly with baseline levels of noncholesterol sterols and proprotein convertase subtilisin-like kexin type 9. Although individual responses varied widely, change in LDL-C on ezetimibe correlated with response to simvastatin (r = 0.46, P < 0.001). Combination therapy lowered LDL-C by 15% or greater in more than 95% of participants.


CONCLUSIONS
Baseline cholesterol absorption and synthesis did not predict responsiveness to LDL-lowering drugs. Responsiveness to simvastatin and ezetimibe were highly correlated, suggesting that factors downstream of the primary sites of action of these drugs are a major determinant of response.
Lakoski
Susan G
SG
Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9046, USA.
Xu
Fang
F
Vega
Gloria L
GL
Grundy
Scott M
SM
Chandalia
Manisha
M
Lam
Chun
C
Lowe
Robert S
RS
Stepanavage
Michael E
ME
Musliner
Thomas A
TA
Cohen
Jonathan C
JC
Hobbs
Helen H
HH
D000328:Adult; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D000069438:Ezetimibe; D006801:Humans; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases / Q000097:blood; D019821:Simvastatin / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D001384:Azetidines; D008078:Cholesterol, LDL; D002784:Cholesterol; D019821:Simvastatin; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D000069438:Ezetimibe