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      Impact of ezetimibe on plasma lipoprotein(a) concentrations as monotherapy or in combination with statins: a systematic review and meta-analysis of randomized controlled trials

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          Abstract

          The aim of this meta-analysis of randomized placebo-controlled clinical trials was to assess the effect of ezetimibe on plasma lipoprotein(a) concentrations. Only randomized placebo-controlled trials investigating the impact of ezetimibe treatment on cholesterol lowering that include lipoprotein(a) measurement were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases (from inception to February 26 th, 2018). A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on lipoprotein concentrations. This meta-analysis of data from 10 randomized placebo-controlled clinical trials (15 treatment arms) involving a total of 5188 (3020 ezetimibe and 2168 control) subjects showed that ezetimibe therapy had no effect on altering plasma Lp(a) concentrations (WMD: −2.59%, 95% CI: −8.26, 3.08, p = 0.370; I 2 = 88.71%, p (Q) < 0.001). In the subgroup analysis, no significant alteration in plasma Lp(a) levels was observed either in trials assessing the impact of monotherapy with ezetimibe versus placebo (WMD: −4.64%, 95% CI: −11.53, 2.25, p = 0.187; I 2 = 65.38%, p (Q) = 0.005) or in trials evaluating the impact of adding ezetimibe to a statin versus statin therapy alone (WMD: −1.04%, 95% CI: −6.34, 4.26, p = 0.700; I 2 = 58.51%, p (Q) = 0.025). The results of this meta-analysis suggest that ezetimibe treatment either alone or in combination with a statin does not affect plasma lipoprotein(a) levels.

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          Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials.

          Elevated lipoprotein(a) (Lp[a]) is a highly prevalent (around 20% of people) genetic risk factor for cardiovascular disease and calcific aortic valve stenosis, but no approved specific therapy exists to substantially lower Lp(a) concentrations. We aimed to assess the efficacy, safety, and tolerability of two unique antisense oligonucleotides designed to lower Lp(a) concentrations.
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            Lipoprotein(a): resurrected by genetics.

            Plasma lipoprotein(a) [Lp(a)] is a quantitative genetic trait with a very broad and skewed distribution, which is largely controlled by genetic variants at the LPA locus on chromosome 6q27. Based on genetic evidence provided by studies conducted over the last two decades, Lp(a) is currently considered to be the strongest genetic risk factor for coronary heart disease (CHD). The copy number variation of kringle IV in the LPA gene has been strongly associated with both Lp(a) levels in plasma and risk of CHD, thereby fulfilling the main criterion for causality in a Mendelian randomization approach. Alleles with a low kringle IV copy number that together have a population frequency of 25-35% are associated with a doubling of the relative risk for outcomes, which is exceptional in the field of complex genetic phenotypes. The recently identified binding of oxidized phospholipids to Lp(a) is considered as one of the possible mechanisms that may explain the pathogenicity of Lp(a). Drugs that have been shown to lower Lp(a) have pleiotropic effects on other CHD risk factors, and an improvement of cardiovascular endpoints is up to now lacking. However, it has been established in a proof of principle study that lowering of very high Lp(a) by apheresis in high-risk patients with already maximally reduced low-density lipoprotein cholesterol levels can dramatically reduce major coronary events. © 2012 The Association for the Publication of the Journal of Internal Medicine.
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              Inhibition of intestinal cholesterol absorption by ezetimibe in humans.

              Ezetimibe has been shown to inhibit cholesterol absorption in animal models, but studies on cholesterol absorption in humans have not been performed thus far. The effect of ezetimibe (10 mg/d) on cholesterol absorption and synthesis, sterol excretion, and plasma concentrations of cholesterol and noncholesterol sterols was investigated in a randomized, double-blind, placebo-controlled, crossover study in 18 patients with mild to moderate hypercholesterolemia. Treatment periods lasted 2 weeks with an intervening 2-week washout period. Fractional cholesterol absorption rates averaged 49.8+/-13.8% on placebo and 22.7+/-25.8% on ezetimibe, indicating a reduction of 54% (geometric mean ratio; P< 0.001). Cholesterol synthesis increased by 89% from 931+/-1027 mg/d on placebo to 1763+/-1098 mg/d on ezetimibe (P<0.001), while the ratio of lathosterol-to-cholesterol, an indirect marker of cholesterol synthesis, was increased by 72% (P<0.001). Bile acid synthesis was insignificantly increased (placebo: 264+/-209 mg/d, ezetimibe: 308+/-184 mg/d; P=0.068). Mean percent changes from baseline for LDL and total cholesterol after ezetimibe treatment were -20.4% and -15.1%, respectively (P<0.001 for both), whereas campesterol and sitosterol were decreased by -48% and - 41%, respectively. In humans, ezetimibe inhibits cholesterol absorption and promotes a compensatory increase of cholesterol synthesis, followed by clinically relevant reductions in LDL and total cholesterol concentrations. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols sitosterol and campesterol, suggesting an effect on the absorption of these compounds as well.
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                Author and article information

                Contributors
                saheb2000@yahoo.com
                sla2002@qatar-med.cornell.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                14 December 2018
                14 December 2018
                2018
                : 8
                : 17887
                Affiliations
                [1 ]ISNI 0000 0001 2198 6209, GRID grid.411583.a, Biotechnology Research Center, Pharmaceutical Technology Institute, , Mashhad University of Medical Sciences, ; Mashhad, Iran
                [2 ]ISNI 0000 0001 2198 6209, GRID grid.411583.a, Neurogenic Inflammation Research Center, , Mashhad University of Medical Sciences, ; Mashhad, Iran
                [3 ]ISNI 0000 0001 2198 6209, GRID grid.411583.a, School of Pharmacy, , Mashhad University of Medical Sciences, ; Mashhad, Iran
                [4 ]ISNI 0000 0001 1091 9430, GRID grid.419157.f, Biomedical Research Unit, , Mexican Social Security Institute, ; Durango, Mexico
                [5 ]ISNI 0000 0004 1757 3630, GRID grid.9027.c, Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, , University of Perugia, ; Perugia, Italy
                [6 ]ISNI 0000 0001 2165 3025, GRID grid.8267.b, Department of Hypertension, WAM University Hospital in Lodz, , Medical University of Lodz, ; Zeromskiego 113, Lodz, Poland
                [7 ]ISNI 0000 0004 0575 4012, GRID grid.415071.6, Polish Mother’s Memorial Hospital Research Institute (PMMHRI), ; Lodz, Poland
                [8 ]ISNI 0000 0004 1936 7910, GRID grid.1012.2, School of Medicine, Faculty of Health and Medical Sciences, , University of Western Australia, ; Perth, Australia
                [9 ]ISNI 0000 0004 0453 3875, GRID grid.416195.e, Lipid Disorders Clinic, Cardiometabolic Services, Department of Cardiology, , Royal Perth Hospital, ; GPO Box X2213 Perth, Australia
                [10 ]Centro Dislipidemie, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy
                [11 ]ISNI 0000 0004 0442 8821, GRID grid.412855.f, Department of Clinical Biochemistry, , Sultan Qaboos University Hospital, ; Muscat, Oman
                [12 ]Weill Cornell Medicine Qatar, Doha, Qatar
                Author information
                http://orcid.org/0000-0002-5887-7257
                Article
                36204
                10.1038/s41598-018-36204-7
                6294784
                30552391
                4a6a121a-372a-4fa8-bd06-c62ab104918e
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 30 April 2018
                : 6 November 2018
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