Efficacy of Ezetimibe 2.5 mg With a Novel Tablet-Splitting Strategy

AJPB® Translating Evidence-Based Research Into Value-Based Decisions®August 2010
Volume 2
Issue 4

This prospective randomized study suggests that ezetimibe 2.5 mg, delivered as an ezetimibe/simvastatin tablet split into 4 parts, is clinically equivalent to a 10-mg dose.

Ezetimibe’s excellent tolerability and ability to lower low-density lipoprotein cholesterol (LDL-C) approximately 20% have made it the most commonly prescribed second-line lipid-lowering agent after statins.1,2 Ezetimibe is available only in a 10-mg form, either as a standalone tablet or in combination with simvastatin as ezetimibe/simvastatin (Vytorin; Merck/Schering-Plough Pharmaceuticals, Whitehouse Station, NJ). During clinical development, a wide range of ezetimibe doses were evaluated, from low doses such as 0.25, 1, and 5 mg to doses as high as 40 mg.3-7 A 2.5-mg dose of ezetimibe was never evaluated.

We previously demonstrated in prospective and retrospective studies that splitting a 10-mg ezetimibe tablet, which provides approximately 5 mg of ezetimibe, is clinically equivalent to a whole 10-mg tablet with respect to its effect on lipid parameters and achievement of LDL-C treatment goals.8,9 On the basis of these results, along with others demonstrating that 1 mg of ezetimibe signifi cantly lowered LDL-C by approximately 13% to 15%,5,6 we prospectively randomized patients to receive simvastatin 20 mg or an ezetimibe/simvastatin 10/80 tablet (10 mg of ezetimibe and 80 mg of simvastatin) divided into 4 parts to yield an estimated daily dose of ezetimibe 2.5 mg and simvastatin 20 mg. We compared the efficacy of the 2 strategies in improving lipid parameters. We selected ezetimibe/simvastatin 10/80 as a means of obtaining 2.5 mg of ezetimibe, as this tablet size can be readily divided into 4 relatively equal parts with a commercially available tablet splitter (the available ezetimibe 10-mg tablet cannot be split into 4 equal parts, based on the personal experience of one of us [LB]).

As comparative effectiveness assumes a central role in medical decision making, the health economic implications of demonstrating the clinical equivalency of the split-tablet strategy in patients converted from a whole tablet is significant to both the millions of patients prescribed ezetimibe and to the payers who spent more than $4 billion on ezetimibe in 2008.10


Our population consisted of Bronx Veterans’ Affairs Medical Center patients whose LDL-C was more than 100 mg/dL and who were not receiving any lipid-lowering therapy. Exclusion criteria were generally related to comorbid conditions (eg, recent myocardial infarction, abnormal liver function, recent surgery, stroke) and a history of intolerance to statins or ezetimibe.

The study was approved by the Institutional Review Board of the Bronx VA Medical Center. After informed consent was obtained, patients were randomized in a blinded manner to a whole simvastatin 20-mg tablet or an ezetimibe/simvastatin 10/80 tablet split into 4 parts. The ezetimibe/simvastatin tablets were split by a research pharmacist, who dispensed all the study medication at one time. The research pharmacist did not weigh the tablets, to simulate clinical practice if this strategy were implemented widely. All study personnel, other than the research pharmacist, were blinded to randomization until the completion of the study.

Total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C) were assessed at baseline and after 6 weeks of therapy. Calculated LDL-C was determined using the Friedewald formula. Non—HDL-C was calculated as total cholesterol minus HDL-C. Compliance with medication during the study period was determined by the pharmacist via pill count, and remained blinded to the investigators until the completion of the study.

Statistical Analysis

The primary variable for analysis was the percentage change from baseline in calculated LDL-C. Secondary analyses included changes in the other lipid parameters: HDL-C, triglycerides, total cholesterol, and non—HDL-C. The impact of the 2 therapies was evaluated using a t test for all lipid values. Baseline characteristics for categorical data were compared using Pearson’s χ2 test with Yates correction. A value of P <.05 was considered significant for all analyses. Assuming a standard deviation of 15% and a 1-sided α of .05, it was determined that 13 patients were needed in each group to provide a statistical power of 80% to detect a 15% between-group difference in calculated LDL-C.


Thirty-four patients were randomized from August 2007 through October 2008. A total of 29 patients successfully completed the protocol (


); 1 patient withdrew from the study after randomization, 2 patients in the ezetimibe/simvastatin group stopped the medication because of myalgias within 10 days of starting the medication, and 1 patient in each group did not return for follow-up. Of the 29 patients, 2 (both in the ezetimibe/ simvastatin cohort) had their follow-up lipid assessment performed prior to 6 weeks, 1 patient after 4 weeks on therapy because of hernia surgery, and 1 patient after 3 weeks of therapy because his primary care physician decided to draw his blood and the subject refused to have his blood redrawn at the final visit.

Baseline characteristics are shown in

Table 1

. Patients in the ezetimibe/simvastatin group tended to be younger. Ezetimibe/simvastatin patients had significant lower HDL-C and non—statistically significantly higher triglycerides. There were no between-group differences in height, weight, presence of diabetes or hypertension, calculated LDL-C, total cholesterol, or non–HDL-C. Compliance was more than 90% in both groups.

Treatment with ezetimibe/simvastatin and simvastatin resulted in statistically and clinically significant reductions from baseline in all lipid parameters except HDL-C (

Table 2

). The additive effect of 2.5 mg of ezetimibe was evident from the clinically meaningful and statistically significant between-group differences in LDL-C, total cholesterol, and non—HDL-C (Table 2). A non–statistically significant reduction in triglycerides also was noted from the ezetimibe contribution. High-density lipoprotein cholesterol decreased in both treatment groups, with a larger and almost statistically significant decrease in the group treated with ezetimibe/simvastatin; HDL-C was the only lipid parameter that did not have a favorable response to the ezetimibe component. Of the 14 ezetimibe/simvastatin-treated patients, 8 (57%) achieved an LDL-C reduction of more than 50%, compared with only 2 of the 15 (13.3%) simvastatin-treated patients.


Ezetimibe is the most commonly prescribed second-line lipid-lowering agent.1,2 Moreover, with respect to annual healthcare expenditures for all lipid-lowering agents, ezetimibe (as a stand-alone tablet or in combination with simvastatin as ezetimibe/simvastatin) ranked second behind atorvastatin, with worldwide sales of more than $4 billion in 2008.10 The economic implications of the ability to switch individual patients from a whole 10-mg tablet to one that is split into 4 parts are considerable.

The almost 18% additional reduction in LDL provided by ezetimibe 2.5 mg in the current study is consistent with the upper end of the effect seen in the 2 largest previous studies comparing simvastatin with ezetimibe/ simvastatin.11,12 In the largest study, ENHANCE, the addition of ezetimibe provided an additional 16.5% reduction in LDL-C.11 In the second largest published study, the addition of ezetimibe to 20 mg of simvastatin provided approximately an additional 18% reduction in LDL-C.12 The fact that our prospective study is consistent with these larger prospective studies provides added proof that 2.5 mg of ezetimibe, delivered as an ezetimibe/simvastatin tablet split into 4 parts, is clinically equivalent to the full 10-mg tablet with respect to lowering LDL-C.

Moreover, a review of ezetimibe use in our institution revealed that the average pre-ezetimibe LDL-C value was 135 mg/dL.8 Using this value as an estimate of the pre-ezetimibe LDL-C and assuming that an additional 3% LDL reduction could be achieved with the additional 7.5 mg provided by the whole 10-mg tablet, the “initial” 2.5 mg would provide an average reduction of 24 mg/dL, whereas the “additional” 7.5 mg would potentially provide a clinically insignificant reduction of 4 mg/dL.

With an average wholesale price of approximately $3 per day for ezetimibe or ezetimibe/simvastatin, the cost for each 1-mg/dL reduction in LDL-C would be 3 cents per day for the initial 2.5 mg of ezetimibe versus 56 cents per day for the additional 7.5 mg, which hardly justifies the added expense. Furthermore, the initial 2.5 mg of ezetimibe seems to provide the vast majority of the LDL-C reduction and is thus the “comparatively effective” dose.

A number of issues surrounding tablet splitting relate to the healthcare system, provider, patient, and tablets. Tablet splitting has been implemented successfully for a number of years as a cost-saving measure in various healthcare settings, including the Department of Veterans Affairs and Kaiser Permanente.13,14 Our prior ezetimibe tablet—splitting studies, which involved an elderly population with a mean age of more than 70 years, demonstrated that even the elderly are capable of splitting ezetimibe.8,9

Splitting a tablet into 4 parts raises issues of patient dexterity and tablet stability. In the current study, a research pharmacist split the tablets. This limitation was by design so as not to introduce a variable that might have affected our ability to assess the effectiveness of the lower ezetimibe dose, the primary outcome measure of the study. The added complexity of splitting the tablets into quarters could reduce the number of patients who are willing and able to split the tablets or increase the number who require additional training. However, the 75% cost savings would appear to justify the additional time and effort that may be required to train patients to split the tablets and to emphasize the significant cost savings achieved with tablet splitting. As the physical size of half an ezetimibe/simvastatin tablet is larger than the intact 10-mg ezetimibe tablet, which is routinely split in our institution, this novel tablet-splitting strategy should be applicable to any patient in whom ezetimibe tablet splitting is being considered.

In the current study, all tablets were split on the first day of the treatment period. This speaks to the stability of the split ezetimibe/simvastatin tablets over time, as the tablets maintained their ability to lower LDL-C for 6 weeks in the split state. Even though the tablets maintained their stability in the split state for 6 weeks, in clinical practice it would seem preferable for patients to split 1 or 2 tablets a week to avoid any potential loss of potency.

To our knowledge, this study represents the first time that a tablet-splitting strategy has been used in which a tablet was split into more than 2 parts. The potential to extend this novel tablet-splitting strategy to other medications for which a wide range of tablet strengths are available (eg, atorvastatin 10, 20, 40, and 80 mg; and irbesartan 75, 150, and300 mg) could result in significant cost savings.

The major limitations of our study are its small sample size and short duration of follow-up. Additional limitations include the select group of patients who were included in the study, specifically a male veteran population from a single center, and the comparison with historical controls for assessing the relative efficacy of the 2.5-mg dose. Despite these limitations, our study is consistent with the LDL-C—lowering effect of ezetimibe in a wide range of studies, including the early dose-finding studies, a larger retrospective analysis, and larger prospective studies.3-9,11,12

The dosing strategy that we are suggesting could be implemented clinically in a number of ways (

Table 3

). One could split the ezetimibe/simvastatin 10/80 tablet into 4 parts and take a quarter of a tablet daily, as described in the current study. Alternatively, those uncomfortable with splitting a tablet into 4 parts could take advantage of the knowledge that alternate-day therapy with ezetimibe and simvastatin provides reductions in LDL-C similar to those of daily therapy, and split either an ezetimibe or an ezetimibe/simvastatin tablet into 2 pieces and take the split tablet every second day.15,16 It must be recognized that alternate-day statin therapy has not been evaluated in cardiovascular outcomes studies. If ezetimibe/simvastatin or ezetimibe were used in such an alternate-day manner, one could supplement with simvastatin in the case of ezetimibe/simvastatin or with any statin in the case of a stand-alone ezetimibe tablet. Increasing the complexity of the dosing regimen with alternate-day therapy could be challenging for a number of patients and result in patients taking too much or too little ezetimibe or statin.

Those patients who fail to achieve their LDL-C goal with 2.5 mg of ezetimibe could be titrated to 5 mg and then 10 mg. If a clinically meaningful reduction in LDL-C were noted after up-titration, they could be maintained on the higher dose, while in the absence of a clinically meaningful benefit the dose could be reduced.


Our study demonstrates that ezetimibe 2.5 mg is an effective dose. From a comparative effectiveness perspective, the 2.5-mg dose provides the greatest value without a clinically meaningful loss of efficacy. Furthermore, this study adds to the evidence base that supports splitting the 5-mg tablet, as the 2.5-mg dose appeared highly effective. With annual ezetimibe/simvastatin and ezetimibe sales of $4 billion, broad implementation of either of these split-tablet ezetimibe dosing strategies could result in an annual cost savings of billions of dollars. If ongoing studies of ezetimibe such as SHARP and IMPROVE-IT demonstrate that ezetimibe reduces cardiovascular events, our findings will remain relevant, as the use of ezetimibe may increase in the future.17,18

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