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Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial.

ABSTRACT: Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were evaluated by multiple regression analysis. No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C response to ezetimibe/simvastatin therapy (beta = 0.020, P = 0.587 for campesterol/TC and beta<0.001, P = 0.992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline, the so-called high absorbers (P < 0.001). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of any posthoc analysis, these results warrant further prospective evaluation in different populations.

SUBMITTER: Jakulj L

PROVIDER: S-EPMC2842149 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial.

Jakulj L L Vissers M N MN Groen A K AK Hutten B A BA Lutjohann D D Veltri E P EP Kastelein J J P JJ

Journal of lipid research 20091014 4

Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campeste ...[more]

PMID: 19828909

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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.

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:IntroductionLong-acting muscarinic antagonists (LAMAs), long-acting β2-agonists (LABAs), inhaled corticosteroids (ICS), and their combinations, are recommended for the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to determine whether the safety and efficacy of aclidinium bromide differs by baseline maintenance LABA and ICS therapies.MethodsASCENT-COPD was a phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium 400 μg or placebo twice daily, via a multidose dry-powder inhaler for up to 3 years. Outcomes included time to first major adverse cardiovascular events (MACE), all-cause mortality, change from baseline in trough forced expiratory volume in 1 s (FEV1), and COPD assessment test (CAT) total score over 3 years, and annual moderate-to-severe COPD exacerbation rate in patients receiving aclidinium or placebo with maintenance LABA monotherapy, ICS monotherapy, LABA + ICS (fixed/free), or no maintenance therapy (neither LABA nor ICS) at baseline.ResultsA total of 3589 patients were included (LABA, n = 227; ICS, n = 290; LABA + ICS, n = 2058; no maintenance, n = 1130). Aclidinium did not increase the risk of MACE or all-cause mortality versus placebo, regardless of baseline maintenance treatment. Reductions in moderate-to-severe exacerbation rates were observed with aclidinium versus placebo in all subgroups [LABA 43% (P = 0.046); ICS 25% (P = 0.202); LABA + ICS 22% (P = 0.003); no maintenance 18% (P = 0.130)]. Aclidinium improved morning trough FEV1 irrespective of baseline therapy and CAT total scores, except for LABA and ICS subgroups, versus placebo at several time points.ConclusionIn patients with moderate-to-severe COPD and CV risk factors, the addition of aclidinium to maintenance therapy with LABA or LABA + ICS provided further benefit.Trial registrationClinicalTrials.gov identifier NCT01966107.

Project description:Treatment 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.Data 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).EZ/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.EZ/Simva is an effective therapeutic option for patients who have not achieved recommended LDL-C treatment targets with simvastatin 20 mg monotherapy.Clinical trial registration numbers: NCT00423488 and NCT00423579.

Project description:Low-density lipoprotein cholesterol (LDL-C) is an important modifiable risk factor for atherosclerotic cardiovascular disease. It is unclear whether the percentage LDL-C lowering with pharmacotherapies differs on the basis of baseline LDL-C levels. To evaluate the association between baseline LDL-C levels and the percentage LDL-C reduction with a statin, ezetimibe, and a PCSK9 inhibitor. This secondary exploratory study analyzed data from 3 randomized placebo-controlled clinical trials (Aggrastat to Zocor-Thrombolysis in Myocardial Infarction 21 [A to Z-TIMI 21], Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT], and Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]) of lipid-lowering therapies (statin, ezetimibe, and a PCSK9 inhibitor) and included participants with atherosclerotic cardiovascular disease. Analyses took place form April to October 2020. In A to Z-TIMI 21, 1:1 randomization to simvastatin, 40 mg, daily for 30 days followed by 80 mg daily thereafter vs placebo for 4 months followed by simvastatin, 20 mg, daily thereafter. In IMPROVE-IT, 1:1 randomization to ezetimibe, 10 mg, daily plus simvastatin, 40 mg, daily vs placebo plus simvastatin, 40 mg, daily. In FOURIER, 1:1 randomization to evolocumab, 140 mg, every 2 weeks or 420 mg monthly vs matching placebo. The percentage LDL-C reduction at either 1 month (A to Z-TIMI 21, IMPROVE-IT) or 3 months (FOURIER) as a function of baseline LDL-C level. Data were modeled using a generalized linear regression model. A total of 3187 patients from A to Z-TIMI 21, 10 680 patients from IMPROVE-IT, and 25 847 patients from FOURIER were analyzed. There was a higher percentage reduction in LDL-C levels with evolocumab in patients with lower baseline LDL-C levels, ranging from 59.4% (95% CI, 59.1%-59.8%) in patients with a baseline LDL-C level of 130 mg/dL to 66.1% (95% CI, 65.6%-66.6%) in patients with a baseline LDL-C level of 70 mg/dL (P < .001). In contrast, across the same range of baseline LDL-C level, there was a more modest difference for simvastatin (44.6% [95% CI, 43.9%-45.2%] vs 47.8% [95% CI, 46.4%-49.2%]; P < .001) and minimal difference with ezetimibe (25.0% [95% CI, 23.3%-26.6%] vs 26.2% [95% CI, 24.2%-28.1%]; P = .007). The percentage LDL-C reduction with statins, ezetimibe, and PCSK9 inhibition is not attenuated in patients starting with lower baseline LDL-C levels and is 6.6% greater for PCSK9 inhibition. These data are encouraging for the use of intensive LDL-C-lowering therapy even for patients with lower LDL-C levels.

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Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial.

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Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial.

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