Safety and efficacy of ezetimibe: A meta-analysis
Introduction
Statins (3 HMG-coA inhibitors) have been proven to reduce cholesterol levels and cardiovascular (CV) events in primary and secondary prevention [1], [2], [3], [4]. Subsequent studies have shown that intensive statin therapy, as compared with less intensive statin therapy, reduces low-density lipoprotein cholesterol (LDL-C) further and produces a greater reduction in CV events [5], [6], [7], [8], [9]. However, there is a significant risk of recurrent CV events even in patients receiving high dose statins, the use of which has also raised safety concerns, leading to the search of additional lipid-modifying therapies [10], [11], [12], [13], [14].
Circulating cholesterol originates from liver synthesis and intestinal absorption, with the latter mechanism increasing its contribution during treatment with statins [15], [16]. Ezetimibe markedly reduces the intestinal absorption of cholesterol interacting with the Niemann–Pick C1-Like 1 (NPC1L1) protein [17], [18]. This results in a further 20–25% reduction in LDL-C levels among patients treated with statins [19], [20]. Should the relationship between LDL-C reduction and cardiovascular events reduction shown by the CTT collaborative study hold true also for ezetimibe [4], this would translate into an additional clinical benefit.
However, a widespread use of ezetimibe has been hindered by the recommendation of the ACC/AHA guidelines to base treatment on statins, in the absence of efficacy data for ezetimibe [21] and by concerns over the safety of this agent, notably over the possibility of an increased incidence of cancer. This originated from the finding of an increased incidence of cancer among patients taking ezetimibe/simvastatin as compared with placebo in the SEAS trial, designed to evaluate the effect of the combination on the progression of aortic stenosis [22]. The publication of a specifically designed safety analysis including data from ongoing trials was not unanimously accepted as appropriate and reassuring [23], leading to a strong controversy [24], [25]. This must not have been completely solved, as suggested by the conclusions on the risk/benefit ratio of ezetimibe reached by a recent meta-analysis published [26]. Notably, this analysis did not include data from the IMPROVE-IT trial [27], [28], [29], [30]. Since this latter trial followed patients for an average of six years providing more than 100,000 patient-year of safety data, approximately the same amount of the combined data included, we thought it would be important to reassess the safety and efficacy of ezetimibe including this essential information.
Section snippets
Search strategy
This study was designed according to the PRISMA (Preferred Reporting Items for Systematic reviews and meta-analyses) statement [31]. MEDLINE, Cochrane Database, ISI Web of Sciences and SCOPUS were searched for articles published in English and other languages until June 2015. Studies were identified by the following headings: ezetimibe, random, randomized controlled trial, and clinical trial. We used reference lists of the retrieved articles and reviews about the current topic as well
Characteristics of included trials
Of 3037 papers identified in the initial search, 167 were retrieved for more detailed evaluation. 160 studies were subsequently excluded. Therefore, 7 trials [22], [30], [38], [39], [40], [41], [42] were finally included in the analysis, which enrolled 31,048 patients (70% males; mean age 61 ± 8 years; mean follow-up 34.1 ± 26.3 months), 15,586 of which were assigned to ezetimibe and 15,462 patients to control therapy (Fig. 1). Baseline characteristics of 7 trials included in the meta-analysis are
Discussion
The findings of the current meta-analysis indicate that ezetimibe significantly reduces the risk of MI and stroke without any significant effect on overall and CV mortality and risk of cancer.
A recent meta-analysis including 7 randomized clinical trials showed a non-significant effect of ezetimibe added to statin on all-cause or CV death, MI, stroke and cancer, suggesting lack of clinical benefit associated with the use of ezetimibe [26]. However, in this analysis SHARP and SEAS trials [22],
Conclusions
Ezetimibe significantly reduces the risk of MI and stroke without any effect on all-cause and CV mortality and risk of cancer.
Conflicts of interest
GdF and PPF received honoraria from Merck Sharp & Dhome for consultant activity and GdF is member of the IMPROVE IT Steering Committee.
Funding
None.
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