Ezetimibe Effectively Reduces Plasma Plant Sterols in Patients With Sitosterolemia
Gerald SalenKlaus von BergmannDieter LütjohannPeter O. KwiterovichJohn P. KaneShailendra B. PatelMing‐Shyan LinPeter H. SteinBeth Musser
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Abstract:
Background— Sitosterolemia is a recessively inherited disorder that results from mutations in either ABCG5 or G8 proteins, with hyperabsorption of dietary sterols and decreased hepatic excretion of plant sterols and cholesterol. As a consequence of markedly elevated plasma and tissue sitosterol and campesterol levels, premature atherosclerosis develops. Methods and Results— In this multicenter, double-blind, randomized, placebo-controlled study, we examined whether treatment with ezetimibe, an inhibitor of cholesterol absorption, reduces plant sterol levels in patients with sitosterolemia. After a 3-week placebo run-in, 37 patients were randomized to receive placebo (n=7) or ezetimibe 10 mg/d (n=30) for 8 weeks. Sitosterol concentrations decreased by 21% ( P <0.001) in patients treated with ezetimibe compared with a nonsignificant 4% rise in those on placebo (between-group P <0.001). The reduction in sitosterol from baseline was progressive, with further decline observed at each subsequent biweekly visit. Campesterol also progressively declined, with a mean decrease after 8 weeks of 24% with ezetimibe and a mean increase of 3% with placebo treatment (between-group P <0.001). Reductions in plant sterol concentrations were similar irrespective of whether patients were undergoing concomitant treatment with resin or statin. Reductions in total sterols and apolipoprotein B were also observed. Ezetimibe was well tolerated, with no serious treatment-related adverse events or discontinuations due to adverse events being reported. Conclusions— Ezetimibe produced significant and progressive reductions in plasma plant sterol concentrations in patients with sitosterolemia, consistent with the hypothesis that ezetimibe inhibits the intestinal absorption of plant sterols as well as cholesterol, leading to reductions in plasma concentrations.Keywords:
Ezetimibe
Plant sterols
Ezetimibe
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To review the primary literature describing the pharmacology of ezetimibe and clinical trials investigating its use in the management of hypercholesterolemia.A MEDLINE search (1966-December 2002) was performed using SCH 48461, SCH 58235, ezetimibe, and 2-azetidinone as key words. English-language articles were identified and the references of these articles were used to further identify pertinent articles and abstracts. Given the paucity of published articles available on ezetimibe, many of the references cited are abstracts.All acquired articles that discussed the pharmacology, pharmacokinetics, chemistry, and clinical efficacy of ezetimibe were reviewed.Articles were selected based on content regarding the medicinal chemistry, pharmacology, and clinical use of ezetimibe.Ezetimibe, approved for use in October 2002, belongs to a new class of antihyperlipidemic agents that uniquely inhibit the absorption of cholesterol by inhibiting the cholesterol transport system located within intestinal cell walls. In humans, ezetimibe reduced cholesterol absorption by >50%. In clinical trials, ezetimibe 10 mg/d reduced low-density lipoprotein cholesterol (LDL-C) by approximately 18% and further enhanced the LDL-C-lowering effect of statin medications by an additional 15-20%. In addition, ezetimibe lowered triglycerides about 5% and increased high-density lipoprotein cholesterol (HDL-C) approximately 3%. Ezetimibe is well tolerated. At present, no serious adverse effects have been directly attributable to ezetimibe.Based on the data currently available, it appears that ezetimibe has a potential role in the treatment of primary hypercholesterolemia; however further data are needed to determine its long-term tolerability and efficacy. The potential roles for ezetimibe include its concurrent use with a statin to further enhance the lowering of LDL-C. Other possible roles for ezetimibe include its concurrent use with a statin to permit a lowering of statin dosage to avoid statin-related complications or its use as monotherapy to treat hypercholesterolemia when statin use cannot be tolerated or is contraindicated. Outcome data demonstrating that cardiovascular morbidity and/or mortality are reduced by ezetimibe therapy have yet to be generated.
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Objective: Ezetimibe is a relatively new lipid lowering agent, which is indicated for the treatment of primary hypercholesterolaemia, either as monotherapy or in combination with other hypolipidaemic drugs. The objective of the present article was to review the side effects attributed to ezetimibe administration and discuss their possible underlying mechanisms. Moreover, we aimed to comment on the possible drug interactions of ezetimibe and present current guidelines regarding its safe use. Methods: Relevant articles were identified through a PubMed search (up to June 2007). Results: Compelling evidence from the majority of the data reviewed here showed that adverse effects associated with ezetimibe use are few and mild without having been associated with serious clinical outcomes. In most studies ezetimibe has not been associated with increased rates of myopathy or rhabdomyolysis, whether used alone or in combination with statins, although there have been some case reports of myopathy attributed to this agent. Moreover, ezetimibe has been associated with mild elevations of liver transaminases, mainly in combination with a statin. Other side effects are extremely rare. It should be noted, however, there are no long-term safety data or outcome studies for ezetimibe yet. Conclusions: Ezetimibe is a safe alternative option for hyperlipidaemic patients intolerant to other lipid lowering drugs as well as a beneficial supplementary agent for patients who do not reach the recommended serum cholesterol level with their current hypolipidaemic treatment. However, as is the case with all new medications, physicians should be alert to recognise adverse effects associated with ezetimibe and report them to regulatory authorities.
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The recent IMPROVE-IT trial clearly showed that lowering serum low-density lipoprotein cholesterol (LDL-C) concentrations via inhibiting intestinal cholesterol absorption through ezetimibe effectively lowered the number of new cardiovascular disease (CVD) events. This supports the use of other (dietary) interventions that lower serum LDL-C concentrations via comparable mechanisms such as described for plant sterol and stanol ester enriched functional foods. Therefore it is tempting to suggest that these compounds may have the same effects on CVD outcome, as described for ezetimibe in the IMPROVE-IT trial. This has however not been proven so far. A possible advantage of plant sterol and stanol ester enriched foods over ezetimibe-a typical single-target drug-is that these dietary compounds act on multiple targets, since they not only lower serum LDL-C concentrations, but also lower serum triacylglycerol (TAG) concentrations in subjects with elevated serum TAG concentrations. In addition, they might influence the functioning of our immune system via a changed activity of the regulatory T-cells. This combination of effects makes these compounds highly attractive to decrease CVD risk.
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Background: Ezetimibe as monotherapy or in combination with statins effectively lowers low-density lipoprotein cholesterol (LDL-C). However, there are few reports of ezetimibe's effect when added to ongoing non-statin lipid-lowering drugs or combination lipid-lowering therapy. Objective: To evaluate the impact of preexisting lipid therapy on LDL-C response to ezetimibe. Methods: We performed a retrospective review of all patients started on ezetimibe therapy at the Veterans Affairs Long Beach Healthcare System between March 1, 2003, and March 1, 2005. We calculated the ezetimibe-induced percent change in LDL-C in patients without concomitant changes in other lipid-lowering medications. We then stratified the population according to the type and number of preexisting lipid therapies and compared the LDL-C–lowering efficacy of ezetimibe among these groups. Results: Overall, ezetimibe was associated with a 23.0% reduction in LDL-C. Patients with preexisting statin monotherapy had significantly greater LDL-C reduction with ezetimibe than did those with preexisting non-statin drugs (–26.1% vs –9.3%; p = 0.0138). In patients with no preexisting lipid therapy (n = 58), monotherapy (n = 115), double therapy (n = 36), or triple therapy (n = 9), ezetimibe decreased LDL-C by 17.3%, 21.4%, 33.5%, and 38.1%, respectively. This stepwise trend in increased ezetimibe efficacy was statistically significant, even with adjustments for baseline LDL-C. Conclusions: Ezetimibe's LDL-C–lowering effects are most pronounced when added to preexisting combination lipid therapy. It appears to be more effective when added to statin therapy compared with other lipid-lowering therapies.
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Results from the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, announced in January 2008, demonstrated that ezetimibe use lowered cholesterol levels but did not slow the progression of atherosclerosis.To examine the association of this announcement with national patterns of ezetimibe prescribing, including medication initiation and discontinuation, as well as predictors of use.Retrospective analysis of a national sample of adults 18 years or older who were continuously enrolled in plans of a large US pharmacy benefit manager from 2007 to 2010.Lipid-lowering therapy prescription claims were categorized as ezetimibe-containing treatments or any other lipid-lowering agent. Initiation was defined as an ezetimibe claim without another in the prior 180 days; discontinuation, as an ezetimibe claim without another in the subsequent 180 days.From 2007 to 2010, 29.1% of the 10,597,296 continuously eligible adults obtained at least 1 lipid-lowering agent prescription. Among these adults, 17.8% were prescribed ezetimibe and 95.3% another lipid-lowering agent, predominantly statins. Ezetimibe use peaked in January 2008, when 2.5% of all adults were ezetimibe users, but declined to 1.8% by December 2010. The ENHANCE trial announcement was associated with a nonsignificant 0.16% fewer monthly ezetimibe users (P = .11) but a significant 0.14% more monthly monotherapy users and 0.30% fewer users of ezetimibe concomitant with other lipid-lowering agents (both P = .01). The ENHANCE trial was also associated with 0.44% fewer monthly ezetimibe initiations (P = .002) and 10.4% more monthly ezetimibe discontinuations (P < .001), particularly of ezetimibe monotherapy for both. More than half of adults who initiated ezetimibe use did so without first being prescribed another lipid-lowering agent, both before (50%-60%) and after (60%-70%) the trial. Those aged 50 to 64 years and those living in the East South Central US Census division were both more likely to initiate and less likely to discontinue ezetimibe after the ENHANCE trial.After announcement of the results of the ENHANCE trial, nearly 2% of all continuously enrolled adult beneficiaries within a large US pharmacy benefit manager used ezetimibe, although ezetimibe initiations declined and discontinuations increased.
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Бұл зерттеужұмысындaКaно моделітурaлы жәнеоғaн қaтыстытолықмәліметберілгенжәнеуниверситетстуденттерінебaғыттaлғaн қолдaнбaлы (кейстік)зерттеужүргізілген.АхметЯссaуи университетініңстуденттеріүшін Кaно моделіқолдaнылғaн, олaрдың жоғaры білімберусaпaсынa қоятынмaңыздытaлaптaры, яғнисaпaлық қaжеттіліктері,олaрдың мaңыздылығытурaлы жәнесaпaлық қaжеттіліктерінеқaтыстыөз университетінқaлaй бaғaлaйтындығытурaлы сұрaқтaр қойылғaн. Осы зерттеудіңмaқсaты АхметЯсaуи университетіндетуризмменеджментіжәнеқaржы бaкaлaвриaт бaғдaрлaмaлaрыныңсaпaсынa қaтыстыстуденттердіңқaжеттіліктерінaнықтaу, студенттердіңқaнaғaттaну, қaнaғaттaнбaу дәрежелерінбелгілеу,білімберусaпaсын aнықтaу мен жетілдіружолдaрын тaлдaу болыптaбылaды. Осы мaқсaтқaжетуүшін, ең aлдыменКaно сaуaлнaмaсы түзіліп,116 студенткеқолдaнылдыжәнебілімберугежәнеоның сaпaсынa қaтыстыстуденттердіңтaлaптaры мен қaжеттіліктерітоптықжұмыстaрaрқылыaнықтaлды. Екіншіден,бұл aнықтaлғaн тaлaптaр мен қaжеттіліктерКaно бaғaлaу кестесіменжіктелді.Осылaйшa, сaпa тaлaптaры төрт сaнaтқa бөлінді:болуытиіс, бір өлшемді,тaртымдыжәнебейтaрaп.Соңындa,қaнaғaттaну мен қaнaғaттaнбaудың мәндеріесептелдіжәнестуденттердіңқaнaғaттaну мен қaнaғaттaнбaу деңгейлерінжоғaрылaту мен төмендетудеосытaлaптaр мен қaжеттіліктердіңрөліaйқын aнықтaлды.Түйінсөздер:сaпa, сaпaлық қaжеттіліктер,білімберусaпaсы, Кaно моделі.
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