Dataset Information

Effect of ezetimibe on low- and high-density lipoprotein subclasses in sitosterolemia.

ABSTRACT: BACKGROUND AND AIMS:Sitosterolemia displays high plasma total sterols [high plant sterols (PS) + normal to high total cholesterol (TC)] with normal to moderately elevated low-density lipoprotein (LDL) levels. High LDL, intermediate-density lipoprotein (IDL) and very low-density lipoprotein (VLDL) particles, low high-density lipoprotein (HDL), and increased non-HDL and the ratios of TC and triglycerides (TG) to HDL can increase the risk for atherosclerosis. Ezetimibe (EZE) can reduce plasma PS and TC levels in sitosterolemia, but its effect on lipoprotein subclasses has not been previously reported. METHODS:Sitosterolemia patients (n = 8) were taken off EZE for 14 weeks (OFF EZE) and placed on EZE (10 mg/d) for 14 weeks (ON EZE). Serum lipids were measured enzymatically and lipoprotein subclasses were assessed by polyacrylamide gel electrophoresis. RESULTS:EZE reduced (p < 0.05) total sterols (-12.5 ± 4.1%) and LDL-sterol (-22.7 ± 5.7%) and its sterol mass of large VLDL (-24.4 ± 4.5%), VLDL remnants (-21.1 ± 7.9%) and large IDL (-22.4 ± 7.2%) compared to OFF EZE. EZE did not affect large LDL subclasses or mean LDL particle size (273.8 ± 0.6 vs. 274.6 ± 0.3 Å). EZE increased HDL-sterol (25.5 ± 8.0%, p = 0.008) including intermediate (34 ± 14%, p = 0.02) and large (33 ± 16%, p = 0.06) HDL. EZE reduced non-HDL-sterol (-21.8± 5.0%), total sterols/HDL (-28.2 ± 5.5%) and TG/HDL (-27.4 ± 6.5%, all p < 0.01). CONCLUSIONS:EZE improves VLDL and HDL subfraction distribution, thereby reducing the atherogenic lipid profile, thus providing potential clinical benefit in sitosterolemia beyond TC and PS reduction.

SUBMITTER: Othman RA

PROVIDER: S-EPMC5419426 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Effect of ezetimibe on low- and high-density lipoprotein subclasses in sitosterolemia.

Othman Rgia A RA Myrie Semone B SB Mymin David D Roullet Jean-Baptiste JB Steiner Robert D RD Jones Peter J H PJH

Atherosclerosis 20170310

<h4>Background and aims</h4>Sitosterolemia displays high plasma total sterols [high plant sterols (PS) + normal to high total cholesterol (TC)] with normal to moderately elevated low-density lipoprotein (LDL) levels. High LDL, intermediate-density lipoprotein (IDL) and very low-density lipoprotein (VLDL) particles, low high-density lipoprotein (HDL), and increased non-HDL and the ratios of TC and triglycerides (TG) to HDL can increase the risk for atherosclerosis. Ezetimibe (EZE) can reduce plas ...[more]

PMID: 28340366

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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.

Project description:ObjectiveStatins are sometimes associated with worsened glycemic control. Patients with type 2 diabetes mellitus (T2DM) may require non-statin therapies to achieve low-density lipoprotein cholesterol (LDL-C) lowering goals. This study evaluated the efficacy and safety of bempedoic acid 180 mg plus ezetimibe 10 mg fixed-dose combination (BA + EZE FDC) in patients with T2DM and hypercholesterolemia who were not receiving background statins or other lipid-lowering therapy.MethodsPatients with T2DM and elevated LDL-C levels were enrolled into this phase 2, double-blind study (NCT03531905). Patients received placebo during a 5-week washout period where background lipid-lowering therapies (including statins) were discontinued. Eligible patients were then randomized 1:1:1 to receive either BA + EZE FDC, ezetimibe 10 mg, or placebo once daily for 12 weeks. Assessments included the percent change from baseline to week 12 in LDL-C, other lipid parameters, and high-sensitivity C-reactive protein (hsCRP); and the monitoring of safety and tolerability.ResultsAmong 179 randomized patients, baseline characteristics following the washout period were similar across treatment groups, with mean LDL-C levels of 142.6 mg/dL and mean glycated hemoglobin of 8.0%. At week 12, BA + EZE FDC therapy lowered mean LDL-C levels by 38.8%, significantly more than ezetimibe alone (19.2%; difference, 19.5% [95% confidence interval (CI), 13.4%-25.7%]; p < 0.001) or placebo (increase of 0.9%; difference, 39.6% [95% CI, 33.4%-45.8%]; p < 0.001). BA + EZE FDC significantly reduced hsCRP levels from baseline vs ezetimibe (29.2%; p = 0.005) and vs placebo (36.7%; p < 0.001). Incidence of treatment-emergent adverse events was low in all treatment groups, with no indication of worsened glycemic control.ConclusionIn patients with T2DM and hypercholesterolemia who were not receiving statins or other lipid-lowering drugs, BA + EZE FDC significantly lowered LDL-C levels and was generally well tolerated.

Project description:BackgroundMixed dyslipidemia [elevated non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides (TGs), and decreased HDL-C] is common in type 2 diabetes mellitus (T2DM) and is associated with increased cardiovascular risk. Non-HDL-C and apolipoprotein B (ApoB) are the preferred therapeutic targets for mixed dyslipidemia. Alirocumab is a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) that effectively reduces low-density lipoprotein cholesterol (LDL-C), non-HDL-C, ApoB, and lipoprotein(a) (Lp[a]), and is well-tolerated in individuals with T2DM.MethodsThe previously reported open-label ODYSSEY DM-DYSLIPIDEMIA trial data demonstrated the effects of alirocumab on individuals with non-HDL-C ≥ 100 mg/dL and TGs ≥ 150 and < 500 mg/dL receiving stable maximally tolerated statin (n = 413). This post hoc subgroup analysis of the primary trial investigated the effects of alirocumab [75 mg every 2 weeks (Q2W) with possible increase to 150 mg Q2W at Week 12] versus usual care [ezetimibe, fenofibrate, or no additional lipid-lowering therapy (LLT)] on non-HDL-C and other lipids in individuals with T2DM and baseline TGs ≥ 200 mg/dL and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women).ResultsAlirocumab significantly reduced non-HDL-C [LS mean difference (standard error (SE)), - 35.0% (3.9)], ApoB [LS mean difference (SE), - 34.7% (3.6)], LDL-C [LS mean difference (SE), - 47.3% (5.2)], LDL particle number [LS mean difference (SE), - 40.8% (4.1)], and Lp(a) [LS mean difference (SE), - 29.9% (5.4)] versus usual care from baseline to Week 24 (all P < 0.0001). Results were similar for alirocumab versus usual care. TG reductions were similar between alirocumab and usual care (no significant difference), but greater with fenofibrate versus alirocumab (P = 0.3371). Overall, alirocumab significantly increased HDL-C versus usual care [LS mean difference (SE), 7.9% (3.6); P < 0.05], although differences with alirocumab versus ezetimibe or fenofibrate were non-significant. Most individuals receiving alirocumab achieved ApoB < 80 mg/dL (67.9%) and non-HDL-C < 100 mg/dL (60.9%). Adverse event frequency was similar between alirocumab (67.2%) and usual care (70.7%). Additionally, no clinically relevant effect of alirocumab on change in glycemic parameters or use of antihyperglycemic agents was observed.ConclusionsAlirocumab is an effective therapeutic option for individuals with T2DM, TGs ≥ 200 mg/dL, and HDL-C < 40 mg/dL (men) or < 50 mg/dL (women). Atherogenic lipid (ApoB and non-HDL) reductions were greater with alirocumab than ezetimibe, fenofibrate, or no LLT. Consistent with previous studies, alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov, NCT02642159. Registered December 24, 2015, https://clinicaltrials.gov/ct2/show/NCT02642159.

Dataset Information

Effect of ezetimibe on low- and high-density lipoprotein subclasses in sitosterolemia.

Publications

Effect of ezetimibe on low- and high-density lipoprotein subclasses in sitosterolemia.

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