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Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men.

ABSTRACT: This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Each treatment period lasted 7 weeks. Ezetimibe and ezetimibe/simvastatin decreased fractional cholesterol absorption by 65% and 59%, respectively (P < 0.001 for both relative to placebo). Simvastatin did not significantly affect cholesterol absorption. Ezetimibe and ezetimibe/simvastatin increased fecal sterol excretion (corrected for dietary cholesterol), which also represents net steady state cholesterol synthesis, by 109% and 79%, respectively (P < 0.001). Ezetimibe, simvastatin, and ezetimibe/simvastatin decreased plasma LDL-cholesterol by 20, 38, and 55%, respectively. The coadministered therapy was well tolerated. The decreases in net cholesterol synthesis and increased fecal sterol excretion yielded nearly additive reductions in LDL-cholesterol for the coadministration of ezetimibe and simvastatin.

SUBMITTER: Sudhop T

PROVIDER: S-EPMC2739752 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men.

Sudhop Thomas T Reber Michael M Tribble Diane D Sapre Aditi A Taggart William W Gibbons Patrice P Musliner Thomas T von Bergmann Klaus K Lütjohann Dieter D

Journal of lipid research 20090420 10

This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Ea ...[more]

PMID: 19380898

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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).

Project description:ObjectiveStatins inhibit cholesterol synthesis but can upregulate cholesterol absorption, with higher doses producing larger effects. Ezetimibe inhibits cholesterol absorption but also upregulates synthesis. We tested whether ezetimibe added to on-going statin therapy would be most effective in lowering LDL-cholesterol (LDL-C) in subjects on high-potency statins and whether these effects would be related to alterations in cholesterol absorption (β-sitosterol) and synthesis (lathosterol) markers.MethodsHypercholesterolemic subjects (n = 874) on statins received ezetimibe 10 mg/day. Plasma lipids, lathosterol, and β-sitosterol were measured at baseline and on treatment. Subjects were divided into low- (n = 133), medium- (n = 582), and high- (n = 159) statin potency groups defined by predicted LDL-C-lowering effects of each ongoing statin type and dose (reductions of ~20-30%, ~31-45%, or ~46-55%, respectively).ResultsThe high-potency group had significantly lower baseline lathosterol (1.93 vs. 2.58 vs. 3.17 μmol/l; p < 0.001) and higher baseline β-sitosterol values (6.21 vs. 4.58 vs. 4.51 μmol/l, p < 0.001) than medium-/low-potency groups. Ezetimibe treatment in the high-potency group produced significantly greater reductions from baseline in LDL-C than medium-/low-potency groups (-29.1% vs. -25.0% vs. -22.7%; p < 0.001) when evaluating unadjusted data. These effects and group differences were significantly (p < 0.05) related to greater β-sitosterol reductions and smaller lathosterol increases. However, LDL-C reduction differences between groups were no longer significant after controlling for placebo effects, due mainly to modest LDL-C lowering by placebo in the high-potency group.ConclusionPatients on high-potency statins have the lowest levels of cholesterol synthesis markers and the highest levels of cholesterol absorption markers at baseline, and the greatest reduction in absorption markers and the smallest increases in synthesis markers with ezetimibe addition. Therefore, such patients may be good candidates for ezetimibe therapy if additional LDL-C lowering is needed.

Project description:BackgroundTreatment guidelines recommend LDL-C as the primary target of therapy in patients with hypercholesterolemia. Moreover, combination therapies with lipid-lowering drugs that have different mechanisms of action are recommended when it is not possible to attain LDL-C targets with statin monotherapy. Understanding which treatment or patient-related factors are associated with attaining a target may be clinically relevant.MethodsData were pooled from two multicenter, randomized, double-blind studies. After stabilization on simvastatin 20 mg, patients with coronary heart disease (CHD) alone and/or type 2 diabetes mellitus (T2DM) were randomized to ezetimibe 10 mg/simvastatin 20 mg (EZ/Simva) or simvastatin 40 mg. The change from baseline in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), TC/HDL-C ratio, triglycerides, and the proportion of patients achieving LDL-C < 2.6 mmol/L (100 mg/dL) after 6 weeks of treatment were assessed, and factors significantly correlated with the probability of achieving LDL-C < 2.6 mmol/L in a population of high cardiovascular risk Italian patients were identified. A stepwise logistic regression model was conducted with LDL-C < 2.6 mmol/L at endpoint as the dependent variable and study, treatment, gender, age (> or = 65 years or < 65 years), as independent variables and baseline LDL-C (both as continuous and discrete variable).ResultsEZ/Simva treatment (N = 93) resulted in significantly greater reductions in LDL-C, TC, and TC/HDL-C ratio and higher attainment of LDL-C < 2.6 mmol/L vs doubling the simvastatin dose to 40 mg (N = 106). Study [including diabetic patients (OR = 2.9, p = 0.003)], EZ/Simva treatment (OR = 6.1, p < 0.001), and lower baseline LDL-C (OR = 0.9, p = 0.001) were significant positive predictors of LDL-C target achievement. When baseline LDL-C was expressed as a discrete variable, the odds of achieving LDL-C < 2.6 mmol/L was 4.8 in favor of EZ/Simva compared with Simva 40 mg (p < 0.001), regardless of baseline LDL-C level.ConclusionEZ/Simva is an effective therapeutic option for patients who have not achieved recommended LDL-C treatment targets with simvastatin 20 mg monotherapy.Trial registrationClinical trial registration numbers: NCT00423488 and NCT00423579.

Project description:Statins are the frontline in cholesterol reduction therapies; however, their use in combination with agents that possess complimentary mechanisms of action may achieve further reductions in low-density lipoprotein cholesterol. Thirty-nine patients were treated with either 80 mg simvastatin (n=20) or 10 mg simvastatin plus 10 mg ezetimibe (n=19) for 6 weeks. Dosing was designed to produce comparable low-density lipoprotein cholesterol reductions, while enabling assessment of potential simvastatin-associated pleiotropic effects. Baseline and post-treatment plasma were analyzed for lipid mediators (eg, eicosanoids and endocannabinoids) and structural lipids by liquid chromatography tandem mass spectrometry. After statistical analysis and orthogonal projections to latent structures multivariate modeling, no changes were observed in lipid mediator levels, whereas global structural lipids were reduced in response to both monotherapy (R(2)Y=0.74; Q(2)=0.66; cross-validated ANOVA P=7.0×10(-8)) and combination therapy (R(2)Y=0.67; Q(2)=0.54; cross-validated ANOVA P=2.6×10(-5)). Orthogonal projections to latent structures modeling identified a subset of 12 lipids that classified the 2 treatment groups after 6 weeks (R(2)Y=0.65; Q(2)=0.61; cross-validated ANOVA P=5.4×10(-8)). Decreases in the lipid species phosphatidylcholine (15:0/18:2) and hexosyl-ceramide (d18:1/24:0) were the strongest discriminators of low-density lipoprotein cholesterol reductions for both treatment groups (q<0.00005), whereas phosphatidylethanolamine (36:3e) contributed most to distinguishing treatment groups (q=0.017). Shifts in lipid composition were similar for high-dose simvastatin and simvastatin/ezetimibe combination therapy, but the magnitude of the reduction was linked to simvastatin dosage. Simvastatin therapy did not affect circulating levels of lipid mediators, suggesting that pleiotropic effects are not associated with eicosanoid production. Only high-dose simvastatin reduced the relative proportion of sphingomyelin and ceramide to phosphatidylcholine (q=0.008), suggesting a pleiotropic effect previously associated with a reduced risk of cardiovascular disease.

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Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men.

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Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men.

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