Dataset Information

Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin.

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.

SUBMITTER: Lakoski SG

PROVIDER: S-EPMC3079219 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Publications

Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin.

Lakoski Susan G SG 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

The Journal of clinical endocrinology and metabolism 20091204 2

<h4>Context</h4>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.<h4>Objective</h4>We tested the hypothesis that individuals with high fractional absorption of cholesterol respond better to the cholesterol absorption inhibitor ezetimibe than to simvastatin, ...[more]

PMID: 19965915

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Project description:Background In randomized trials (SHARP [Study of Heart and Renal Protection], IMPROVE -IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), combination of statin and ezetimibe resulted in additional reduction of cardiovascular events. The reduction was greater in patients with type 2 diabetes mellitus (T2 DM ), where elevated remnant cholesterol and high cardiovascular disease risk is characteristic. To evaluate possible causes behind these results, 40 patients eligible for cholecystectomy, randomized to simvastatin, ezetimibe, combined treatment (simvastatin+ezetimibe), or placebo treatment during 4 weeks before surgery, were studied. Methods and Results Fasting blood samples were taken before treatment start and at the end (just before surgery). Bile samples and liver biopsies were collected during surgery. Hepatic gene expression levels were assessed with qPCR . Lipoprotein, apolipoprotein levels, and content of cholesterol, cholesteryl ester, and triglycerides were measured after lipoprotein fractionation. Lipoprotein subclasses were analyzed by nuclear magnetic resonance. Apolipoprotein affinity for human arterial proteoglycans ( PG ) was measured. Biomarkers of cholesterol biosynthesis and intestinal absorption and bile lipid composition were analyzed using mass spectrometry. Combined treatment caused a statistically significant decrease in plasma remnant particles and apolipoprotein B (ApoB)/lipoprotein content of cholesterol, cholesteryl esters, and triglycerides. All treatments reduced ApoB-lipoprotein PG binding. Simvastatin and combined treatment modified the composition of lipoproteins. Changes in biomarkers of cholesterol synthesis and absorption and bile acid synthesis were as expected. No adverse events were found. Conclusions Combined treatment caused atheroprotective changes on ApoB-lipoproteins, remnant particles, bile components, and in ApoB-lipoprotein affinity for arterial PG . These effects might explain the decrease of cardiovascular events seen in the SHARP and IMPROVE - IT trials. Clinical Trial Registration URL : www.clinicaltrialsregister.eu . Unique identifier: 2006-004839-30).

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Dataset Information

Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin.

Context

Objective

Design, setting, and participants

Intervention

Main outcome

Results

Conclusions

Publications

Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin.

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