Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin

Susan G. Lakoski, Fang Xu, Gloria L Vega, Scott M Grundy, Manisha Chandalia, Chun Lam, Robert S. Lowe, Michael E. Stepanavage, Thomas A. Musliner, Jonathan C Cohen, Helen H Hobbs

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)800-809
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume95
Issue number2
DOIs
StatePublished - Feb 2010

Fingerprint

Simvastatin
Metabolism
LDL Cholesterol
Cholesterol
Proprotein Convertases
Placebos
Pharmaceutical Preparations
Anticholesteremic Agents
Sterols
Ezetimibe
Hypercholesterolemia
Ethnic Groups
African Americans
Cross-Over Studies
Coronary Artery Disease
Biomarkers
Plasmas
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin. / Lakoski, Susan G.; Xu, Fang; Vega, Gloria L; Grundy, Scott M; Chandalia, Manisha; Lam, Chun; Lowe, Robert S.; Stepanavage, Michael E.; Musliner, Thomas A.; Cohen, Jonathan C; Hobbs, Helen H.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 95, No. 2, 02.2010, p. 800-809.

Research output: Contribution to journalArticle

Lakoski, Susan G. ; Xu, Fang ; Vega, Gloria L ; Grundy, Scott M ; Chandalia, Manisha ; Lam, Chun ; Lowe, Robert S. ; Stepanavage, Michael E. ; Musliner, Thomas A. ; Cohen, Jonathan C ; Hobbs, Helen H. / Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin. In: Journal of Clinical Endocrinology and Metabolism. 2010 ; Vol. 95, No. 2. pp. 800-809.
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abstract = "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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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

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