TY - JOUR
T1 - Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin
AU - Lakoski, Susan G.
AU - Xu, Fang
AU - Vega, Gloria L
AU - Grundy, Scott M
AU - Chandalia, Manisha
AU - Lam, Chun
AU - Lowe, Robert S.
AU - Stepanavage, Michael E.
AU - Musliner, Thomas A.
AU - Cohen, Jonathan C
AU - Hobbs, Helen H
N1 - Funding Information:
This work was supported by the Donald W. Reynolds Foundation and Merck and Co., Inc.
PY - 2010/2
Y1 - 2010/2
N2 - Context: 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. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, crossover trial was performed in 215 African- and European-American men. Intervention: Participants were randomized to placebo, ezetimibe (10 mg/d), simvastatin (10 mg/d), and both drugs for 6 wk each. Main Outcome: 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.
AB - Context: 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. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, crossover trial was performed in 215 African- and European-American men. Intervention: Participants were randomized to placebo, ezetimibe (10 mg/d), simvastatin (10 mg/d), and both drugs for 6 wk each. Main Outcome: 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.
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U2 - 10.1210/jc.2009-1952
DO - 10.1210/jc.2009-1952
M3 - Article
C2 - 19965915
AN - SCOPUS:76149129688
SN - 0021-972X
VL - 95
SP - 800
EP - 809
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 2
ER -