Clinical research
Co-administration of ezetimibe and a statin in management of dyslipidemias: a meta-analysis of clinical trials

Introduction
Coronary heart disease (CHD) remains a leading cause of mortality with significant burden of illness in the western world [1, 2]. The direct association between plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and risk for CHD [3-5] and cardiovascular disease (CVD) [5-8] has been well established. Several studies have demonstrated that cardiovascular mortality risk is reduced with lower LDL-C plasma levels [5, 9, 10]. An estimated 36 million adults in the United States with elevated levels of total cholesterol (TC) and LDL-C will require lipid-lowering drug therapy in order to achieve the recommended target goals established by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) [11].
Lifestyle modifications including diet and exercise have been shown to be effective in producing decreases in LDL-C [12], however, for clinically significant and sustained reductions in LDL-C, concurrent medication use is the most important factor in achieving appropriate LDL-C values [13]. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are used as first-line pharmacological therapy for the treatment of hypercholesterolemia with a predominant focus on the reduction of LDL-C [14]. Statins reduce the endogenous production of cholesterol by blocking the first step in the HMG-CoA reductase pathway. The use of statin monotherapy in several large randomized trials has been shown to significantly reduce plasma LDL-C up to 60% [15]. Despite their well documented efficacy, recent studies have shown that an important percentage of high risk patients on statin therapy remain above LDL-C target levels [14, 16, 17]. Possible explanations for this observation include poor adherence and compliance with treatment as well as low tolerability for high-dose statin use [18-20]. In addition, although statins act to inhibit the biosynthesis of cholesterol, they do not affect the absorption of exogenous cholesterol originating from dietary intake. In recognition of the above, combined pharmacological treatment that inhibits both the hepatic biosynthesis and intestinal absorption of cholesterol may prove more effective than statin monotherapy in reducing cholesterol and achieving recommended LDL-C targets.
Ezetimibe is a compound which selectively inhibits cholesterol absorption by binding to the Niemann-Pick C1-like 1 (NPC1L1) protein [21]. It is located in the small intestine, where it contributes substantially to the intestinal uptake and cellular transport of cholesterol by preventing its passage across the intestinal wall [22].
The mechanism of action of ezetimibe is complementary to that of statins in the prevention of serum cholesterol accumulation. Therefore, the purpose of this study was to synthesize the evidence generated in randomized clinical trials that evaluated the effectiveness of either coadministering ezetimibe 10 mg/day with an existing statin or of simultaneous treatment initiation of ezetimibe with a statin.

Material and methods
Data sources and search strategy
Identification of potentially eligible articles involved a search of the PubMed and MEDLINE databases using the keywords “ezetimibe” and “statin”. The search was conducted between June 1, 2006 and December 1, 2006 and was restricted to “human subjects” and articles written in the “English language”. It was further limited to “core clinical journals”, “randomized controlled trials” and “articles added to PubMed or MEDLINE within the last ten years”. The abstracts of the identified articles were retrieved and reviewed for eligibility.
In order to be selected for further review, the publications had to report results from randomized controlled trials that assessed either the efficacy of ezetimibe coadministered with a statin in patients who had been on statin monotherapy, or ezetimibe coadministered with a statin in patients who were treatment-naI¨ve or washed out of any lipid-lowering medication (LLMs) prior to study entry. All trials must have reported plasma LDL-C at baseline and either the mean percent change in LDL-C from baseline or post-treatment plasma LDL-C values. Assessment of eligibility and data extraction for each study were conducted independently by three investigators (J.A., N.K., and J.S.S.). Only full, peer-reviewed publications reporting the results of original clinical trials were reviewed. Abstracts and conference proceedings were not included. Disagreements between the three reviewers were resolved by consensus.
When more than one manuscript reporting results from the same study were identified, they were combined into one record using the most complete and recent data. For each study, the following data were extracted: sample size, mean age of patient population, prevalence of related comorbidity, specifically, diabetes mellitus, coronary artery disease, CVD, and hypertension, statin(s) used, statin dose and duration of statin treatment. Outcome data extracted were baseline lipid parameters and percent change in baseline lipid parameters, specifically, LDL-C, TC, TG, high-density lipoprotein cholesterol (HDL-C), and the TC/HDL-C ratio. Data were abstracted only from the published results of the identified trials. No other data sources were used.
Percent changes in lipid parameters as reported in the publication were confirmed from the raw data where possible. When percent changes were not reported, they were estimated from the data available. Percent changes for the longest duration of treatment were used when multiple observations were available. If patients had their statin dose titrated, the percent changes for sequential durations of treatment were treated as independent observations. Standard deviations (SD) of the percent change in lipid parameters were used where reported. When not reported, the SD of the change was imputed as the weighted average of the SD from other studies where the SD was reported.

Statistical analysis
The primary outcome measure was the percent change in LDL-C from baseline. In patients who were previously on statin therapy, baseline was defined as the time prior to the addition of ezetimibe to ongoing statin therapy. In patients who were washed out from their previous LLMs or treatment-naI¨ve, baseline was defined as the time prior to initiation of treatment with statin and ezetimibe simultaneously. Secondary outcome measures included the percent change from baseline in TC, TG, HDL-C and TC/HDL-C during the treatment period. TG values were reported as both means and medians. In the event that a manuscript did not specify whether TG values were reported as a mean or a median, they were assumed to be means. When only medians were reported, this value was used to replace the mean in the calculation of the overall effect. The standard deviations of the post-treatment mean LDL-C values were often not reported and therefore, were assumed to be equal to the standard deviation of the baseline means.
In estimating the overall effect across studies, the weight for each study was calculated as the inverse of the variance of the mean change in the lipid parameters assessed. The overall variance across studies was calculated as the inverse of the sum of weights and the standard error (SE) was the square root of the variance. A fixed-effect analysis was performed. The overall effect size was estimated as the weighted mean percent change across all studies. Ninety-five percent confidence intervals (95% CI) of the overall effect size were estimated assuming a normal distribution. All analyses were conducted using the software A Comprehensive Meta-Analysis 2.0. Weighted means were used to describe the age of subjects and the duration of treatment across all studies. Comorbidities were aggregated as weighted mean proportions across all studies where individual comorbidities were reported.

Results
Selection of studies for review
Of the 757 potentially eligible publications identified from the initial search, 739 were excluded because they did not fulfill the initial screening criteria. There were eighteen reports of clinical trials selected for final review. Of these, two were excluded because LDL-apheresis was used [23, 24] and one because it reported results of a subgroup-analysis from a randomized controlled clinical trial that was already reported elsewhere [25]. The remaining fifteen clinical trials were included in this review (Figure 1) [26-40].
Of the fifteen included trials, six [30, 31, 33, 35, 38, 40] reported results for patients who were previously on a statin monotherapy prior to study entry and nine [26-29, 32, 34, 36, 37, 39] reported results for patients who were treatment-naI¨ve or washed out from any previous LLMs prior to study entry. In total, six different statins were coadministered with ezetimibe in the studies reviewed, specifically, atorvastatin, simva- statin, pravastatin, lovastatin, cerivastatin and fluvastatin. Three trials reported results exclusively for atorvastatin [26, 27, 31], eight for simvastatin [28-30, 32-35, 37, 38], one for pravastatin [39] and one for lovastatin [37]. Two trials reported results for more than one statin [35, 40]. There were no studies exclusively assessing cerivastatin or fluvastatin. The studies were classified into the following three groups according to the statin used: atorvastatin, simvastatin and combination/other. The com-bination/other group included trials that reported pooled results for more than one statin and those that reported results for lovastatin [37] and pravastatin [39].
The description of the trials included in the analysis is summarized in Table I. All trials were double-blind, with the exception of one in which only patients were blinded to the treatment [34].

Study population and treatment groups
A total of 5,489 patients included in the studies reviewed were on statin monotherapy prior to study entry for a minimum of 6 weeks. Their mean (SD) duration of statin treatment was 6.9 (2.1) weeks and ranged from 6 to 12 weeks. In these studies, 3,376 patients received ezetimibe coadministered with a statin and 2,113 were treated with statin monotherapy. A total of 6,209 patients were treatment-naI¨ve or washed out from any LLMs prior to study entry. Of these, 3,413 were treated with a statin plus ezetimibe combination regimen and 2,796 were treated with statin monotherapy. The mean (SD) duration of treatment was 13.6 (12.1) weeks with a range between 5 to 52 weeks (Table I).
For the patients treated with statin monotherapy prior to study entry, the mean age and reported comorbidities were similar for those receiving a statin and ezetimibe coadministration regimen and those receiving statin monotherapy (Table IIa). The mean age and comorbidities reported in patients who were treatment-naI¨ve or washed out from previous LLMs were also similar between treatment groups (Table IIb). However, patients treated with statin monotherapy prior to study entry were slightly older and presented more comorbidities than patients who were treatment-naI¨ve or washed out from previous LLMs prior to study entry (Tables IIa, IIb).

Change in LDL-C
Overall effect
For the 3,376 patients who were treated with a statin plus ezetimibe coadministration regimen in the studies where ezetimibe was added to ongoing statin monotherapy, the weighted mean (SD) baseline serum LDL-C was 129.6 (31.8) mg/dl (95% CI 128.5 to 130.7 mg/dl) and the mean (SD) post-treatment LDL-C was 95.2 (31.8) mg/dl (95% CI 94.1 to 96.3 mg/dl) (Table IIIa). This is equivalent to an overall mean percent LDL-C change from baseline of –27.1% (95% CI –27.9 to –26.4%) (Table IIIa and Figure 2a). For the 2,113 patients in these studies treated with statin monotherapy, the weighted mean (SD) baseline plasma LDL-C was 129.2 (26.6) mg/dl (95% CI 127.4 to 131.0 mg/dl) and the mean (SD) post-treatment serum LDL-C was 123.3 (26.6) mg/dl (95% CI 121.3 to 125.1 mg/dl) (Table IIIa). This is equivalent to a change in LDL-C from baseline of –4.5% (95% CI –5.3 to -3.8%) (Table IIIa, Figure 2b).
In the studies that required patients to be treatment-naI¨ve or to be washed out from LLMs prior to study entry, a total of 3,413 patients were treated with a statin plus ezetimibe coadministration therapy. For these patients, the mean (SD) baseline serum LDL-C level was 176.5 (31.2) mg/dl (95% CI 175.5 to 177.5 mg/dl) and the post-treatment mean (SD) LDL-C level was 86.5 (31.2) mg/dl (95% CI 85.5 to 87.5 mg/dl) (Table IIIb). A total of 2,796 patients in these studies were treated with statin monotherapy. These patients had a mean (SD) baseline serum LDL-C of 178.1 (31.5) mg/dl (95% CI 176.9 to 179.3 mg/dl) and a mean post treatment LDL-C level of 107.8 (31.5) mg/dl (95% CI 106.6 to 109.0 mg/dl). These changes represent an overall mean percent change in LDL-C of –51.5% (95% CI –51.9 to –51.1%) for the statin plus ezetimibe coadministration regimen and of –40.4% (95% CI –40.9 to –40.0%) for statin monotherapy (Table IIIb, Figures 3a, 3b, respectively).

Change in HDL-C
Overall effect
For the 3,376 patients who were treated with a statin plus ezetimibe coadministration regimen in the studies where ezetimibe was added to ongoing statin monotherapy, the weighted mean (SD) baseline serum HDL-C was 49.1 (11.7) mg/dl and the mean (SD) post-treatment HDL-C was 50.2 (11.7) mg/dl (Table IIIa). This is equivalent to an overall mean percent HDL-C change from baseline of 1.8% (Table IIIa). For the 2,113 patients in these studies treated with statin monotherapy, the weighted mean (SD) baseline plasma HDL-C was 50.4 (12.6) mg/dl and the mean (SD) post-treatment serum HDL-C was 50.5 (12.6) mg/dl (Table IIIa). This is equivalent to a change in HDL-C from baseline of –0.1% (Table IIIa).
For the 3,413 patients in the treatment-naI¨ve category were treated with a statin plus ezetimibe coadministration therapy, the mean (SD) baseline serum HDL-C level was 49.0 (12.3) mg/dl and the post-treatment mean (SD) HDL-C level was 52.8 (12.3) mg/dl (Table IIIb). A total of 2,796 patients in these studies were treated with statin monotherapy. These patients had a mean (SD) baseline serum HDL-C of 49.4 (12.0) mg/dl and a mean post treatment HDL-C level of 52.1 (12.0) mg/dl. These changes represent an overall mean percent change in LDL-C of 8.7% for the statin plus ezetimibe coadministration regimen and of 5.6% for statin monotherapy (Table IIIb).
Tables IIIa and IIIb also summarize the mean percent changes in TC, TG, and TC/HDL-C observed in the studies reviewed. Across all patient populations, ezetimibe coadministered with statin produced higher reductions in TC, TG and TC/HDL-C when compared to statin monotherapy.

Discussion
Epidemiological studies and clinical trials have confirmed the association between elevated levels of LDL-C and increased risk for CHD. More recently, attention has been given to the potential beneficial effects of higher levels of HDL-C in the prevention of CHD. Therefore, optimal preventive interventions would reduce LDL-C and increase HDL-C [3-5].
Through the complementary action offered by statin and ezetimibe coadministration, the likelihood of achieving LDL-C goals in hypercholesterolemic patients is increased significantly when compared to statin monotherapy [26, 32]. In the EASE trial, 71% of patients reached their NCEP ATP III LDL-C goal when ezetimibe was added to their statin therapy, compared with only 21% of patients who reached their goal when a placebo was added to their statin regimen [40]. As a result, itis expected that a higher proportion of patients will achieve their recommended target LDL-C goals if treated with combination therapy. In patients who fail to reach their lipid goal while on statin monotherapy, combination therapy with ezetimibe provides an alternative to titrating the statin dose, which has been associated with an increased incidence of adverse events [26, 32, 35, 41].
Beyond LDL-C, evidence has shown that high HDL-C protects against CHD, and that low blood levels of HDL-C indicate high risk of a coronary event [42]. Low HDL-C is widely prevalent in the United States [42]. In recognition of its anti-atherogenic effects, recent guidelines have increased the threshold for defining low levels of HDL-C for both men and women [42]. Gordon et al. showed that an increase in HDL-C of 1 mg/dl equates with a 2% relative risk reduction in the incidence of coronary events in men and 3% in women [41]. These observations suggest that, in order to properly reduce morbidity and mortality due to CHD, pharmacological increases in HDL-C should, also be targeted in the prevention of CHD.
In the studies reviewed, two possible approaches to the management of hypercholesterolemia were assessed. One involves the addition of ezetimibe to existing statin monotherapy in patients who fail to reach their treatment goals, while the other involves the simultaneous administration of a statin plus ezetimibe regimen in treatment-naI¨ve patients. The addition of ezetimibe to patients previously on a statin therapy produced less of a reduction in serum LDL-C when compared to the simultaneous administration of both these agents in patients washed out from previous LLMs. The difference in baseline LDL-C values would explain the higher mean percent change observed in treatment-naI¨ve patients or washed out patients from their previous LLMs. This difference is explained by the effect of prior statin monotherapy in lowering LDL-C. Once patients have been washed out, lipid profiles return to pre-treatment levels. Therefore, a greater baseline change was observed in this population as their baseline LDL-C levels were higher. Patients who were on statin monotherapy and had ezetimibe added-on, have baseline LDL-C levels reflective of the effect of their statin therapy. However, both groups attained similar post-treatment LDL-C levels of < 100 mg/dl.
When compared to statin monotherapy, statin coadministered with ezetimibe was found to produce greater reductions in plasma LDL-C. While both treatment groups had similar baseline values, they differed in their post-treatment LDL-C values as the combination therapy group was reduced to 83.0 mg/dl and the monotherapy group, to 103.0 mg/dl. These results indicate that the post- treatment LDL-C values in patients treated with statin plus ezetimibe combination therapy were, on average, significantly lower than the recommended 100 mg/dl LDL-C target set by current treatment guidelines. Evans et al. suggested that, for every 38.6 mg/dl decrease in LDL-C values in patients treated with statins, regardless of baseline LDL-C values, an estimated 25% reduction in cardiovascular risk can be expected [44]. Applying this model to the results of this meta-analysis, the 20 mg/dl difference observed between the combination therapy and monotherapy groups would result in an estimated 13% additional cardiovascular risk reduction. Recently, two studies have been released regarding the effects of ezetimibe on cardiovascular outcomes. The ENHANCE [21, 45] and SEAS [46] studies set out to assess the effect of ezetimibe on the rate of atherosclerosis progression and aortic valve stenosis respectively. Although these studies failed to show ezetimibe having any effect on these cardiovascular outcomes, the SEAS study showed a reduction in the risk of ischemic cardiovascular events in patients taking combination therapy. Also, the validity of the results in the ENHANCE trial have been questioned for numerous reasons. Firstly, change in carotid intima-media thickness (IMT) in the study population was probably not an effective surrogate for the rate of cardiovascular clinical events. Also, most individuals in the study had been under previous treatment with a statin making it more difficult to improve their baseline IMT [47]. Ezetimibe related cardiovascular outcomes are currently the subject of ongoing outcomes trials. Also, the effect this drug has on mortality in this population remains to be fully evaluated by the IMROVE-IT trial which should be available in 2011 [47].

Limitations
A potential limitation of the current meta analysis is that for a small number of studies, certain assumptions were made for the estimation of variance and standard deviations. This could lead to biased estimates of effect. This manuscript relates to short term data, with a mean duration of treatment of 13.6 weeks in patients who were treatment naI¨ve or washed out of any LLMs and a mean duration of treatment of 6.9 weeks in patients that were on statin monotherapy prior to study entry. Due to the well-documented differences in medication adherence in short and long term studies, data regarding long term efficacy of treatment with ezetimibe and statin are needed.
In conclusion, the aim of this study was to look at the effect of ezetimibe/statin coadministration with a focus on biomarkers traditionally used for the approval of lipid lowering medications. The results indicate that adding ezetimibe to ongoing statin therapy is efficient in reducing serum LDL-C in patients who may not attain target levels on statin therapy alone. They also indicate that the simultaneous administration of a statin plus ezetimibe regimen in patients who are treat-ment-naI¨ve is also efficient at reducing plasma LDL-C.

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