CLINICAL STUDY
Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia
Michael H. Davidson, MD, FACC*,*,
Thomas McGarry, MD, FACC ,
Robert Bettis, MD ,
Lorenzo Melani, MD, PhD ,
Leslie J. Lipka, MD, PhD, FACC,
Alexandre P. LeBeaut, MD,
Ramachandran Suresh, PhD,
Steven Sun, PhD,
Enrico P. Veltri, MD, FACC Ezetimibe Study Group
* Chicago Center for Clinical Research, Chicago, Illinois, USA
Oklahoma Foundation for Cardiovascular Research, Oklahoma City, Oklahoma, USA
Clinical Research Advantage, Edmonds Family Medicine Clinic, Edmonds, Washington, USA
Schering-Plough Research Institute, Kenilworth, New Jersey, USA
Manuscript received April 11, 2002;
revised manuscript received September 6, 2002,
accepted September 20, 2002.
* Reprint requests and correspondence: Dr. Michael H. Davidson, Chicago Center for Clinical Research, 515 North State Street, Suite 2700, Chicago, Illinois 60610-4324 USA.
mdavidson{at}protocare.com
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Abstract
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OBJECTIVES: The purpose of this study was to assess the efficacy and safety of ezetimibe administered with simvastatin in patients with primary hypercholesterolemia.
BACKGROUND: Despite the availability of statins, many patients do not achieve lipid targets. Combination therapy with lipid-lowering agents that act via a complementary pathway may allow additional patients to achieve recommended cholesterol goals.
METHODS: After dietary stabilization, a 2- to 12-week washout period, and a 4-week, single-blind, placebo lead-in period, patients with baseline low-density lipoprotein cholesterol (LDL-C)  145 mg/dl to  250 mg/dl and triglycerides (TG) 350 mg/dl were randomized to one of the following 10 groups administered daily for 12 consecutive weeks: ezetimibe 10 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg plus simvastatin 10, 20, 40, or 80 mg; or placebo. The primary efficacy variable was percentage reduction from baseline to end point in direct LDL-C for the pooled ezetimibe plus simvastatin groups versus pooled simvastatin groups.
RESULTS: Ezetimibe plus simvastatin significantly improved LDL-C (p < 0.01), high-density lipoprotein cholesterol (HDL-C) (p = 0.03), and TG (p < 0.01) compared with simvastatin alone. Ezetimibe plus simvastatin (pooled doses) provided an incremental 13.8% LDL-C reduction, 2.4% HDL-C increase, and 7.5% TG reduction compared with pooled simvastatin alone. Coadministration of ezetimibe and simvastatin provided LDL-C reductions of 44% to 57%, TG reductions of 20% to 28%, and HDL-C increases of 8% to 11%, depending on the simvastatin dose. Ezetimibe 10 mg plus simvastatin 10 mg and simvastatin 80 mg alone each provided a 44% LDL-C reduction. The coadministration of ezetimibe with simvastatin was well tolerated, with a safety profile similar to those of simvastatin and of placebo.
CONCLUSIONS: When coadministered with simvastatin, ezetimibe provided significant incremental reductions in LDL-C and TG, as well as increases in HDL-C. Coadministration of ezetimibe with simvastatin was well tolerated and comparable to statin alone.
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Abbreviations and Acronyms
| | ALT | | alanine aminotransferase | | AST | | aspartate aminotransferase | | CPK | | creatine phosphokinase | | HDL-C | | high-density lipoprotein cholesterol | | LDL-C | | low-density lipoprotein cholesterol | | NCEP ATP | | National Cholesterol Education Program Adult Treatment Panel | | TC | | total cholesterol | | TG | | triglycerides | | ULN | | upper limit of normal |
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Despite the impressive low-density lipoprotein cholesterol (LDL-C)–lowering efficacy of statins, the most commonly prescribed cholesterol-lowering agents, a substantial percentage of patients require additional LDL-C reduction beyond that achieved by current statin regimens to attain the target levels recommended by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) (1). Combination drug therapy with currently available lipid-modifying agents (e.g., statins, fibric acid derivatives, bile acid sequestrants, and niacin) may offer a significant advantage over monotherapy, potentially allowing more patients to achieve target cholesterol goals. However, combination therapy is often limited by an increased risk of side effects, intolerance, noncompliance, or drug interactions (2–6).
Ezetimibe is a member of a new class of lipid-altering agents that inhibits the absorption of dietary and biliary cholesterol without affecting the absorption of triglycerides (TG) or fat-soluble vitamins (7–9). Because ezetimibe inhibits the intestinal absorption of cholesterol (the molecular mechanism of action of ezetimibe is currently being investigated), it was hypothesized that the lipid-altering effect of ezetimibe might be complementary to that of agents that inhibit synthesis of cholesterol, such as statins. Results from two pilot clinical pharmacology studies assessing the pharmacokinetic and pharmacodynamic interaction between ezetimibe and simvastatin in subjects with primary hypercholesterolemia suggested that coadministration of these two agents had an additive effect on LDL-C reduction, did not affect the pharmacokinetics of simvastatin, and was safe and well tolerated (10,11).
The study reported here was designed to assess whether ezetimibe 10 mg coadministered with simvastatin in patients with primary hypercholesterolemia, versus treatment with simvastatin alone, produced incremental reductions in LDL-C while maintaining a similar safety profile. Secondary objectives were to evaluate the change from baseline for additional lipid variables. Additionally, the proportions of patients reaching NCEP ATP II and ATP III target levels for direct LDL-C at study end point were examined in an exploratory manner.
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Methods
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Patients.
This was a multicenter trial conducted at 61 study centers in the U.S. The protocol was reviewed and approved by each institution’s Institutional Review Board or Independent Ethics Committee. All patients provided written informed consent. Men and women ages 18 years and older with primary hypercholesterolemia (plasma LDL-C concentration 145 mg/dl to 250 mg/dl, as calculated by the Friedewald equation [12], and TG 350 mg/dl) were considered eligible for study participation.
Prohibited concomitant illnesses and procedures included congestive heart failure (defined as New York Heart Association class III or IV heart failure) (13); uncontrolled cardiac arrhythmias; history of unstable or severe peripheral artery disease within three months of study entry; unstable angina pectoris; myocardial infarction, coronary bypass surgery, or angioplasty within six months of study entry; uncontrolled or newly diagnosed (within one month of study entry) diabetes mellitus; active or chronic hepatic or hepatobiliary disease; known impairment of renal function; known coagulopathy; and unstable endocrine disease.
Study design
This multicenter, randomized, double-blind, placebo-controlled, 2 x 5 factorial study consisted of three phases (Fig. 1). During the 2- to 12-week washout period, all lipid-altering drugs were discontinued, and patients were instructed regarding the NCEP Step I (or stricter) diet (14). The subsequent four weeks constituted the single-blind, placebo lead-in period. At Visit 2 (Q1) and Visit 3 (Q2), blood samples were collected to assay for qualifying lipid values; the mean value of plasma LDL-C for Q1 and Q2 had to be 145 mg/dl and 250 mg/dl, with no single value <145 mg/dl or >250 mg/dl. At Visit 4, qualifying patients were randomized to receive one of the following 10 treatments administered orally once daily for 12 consecutive weeks: ezetimibe 10 mg (Merck/Schering-Plough Pharmaceuticals, Inc., Kenilworth, New Jersey); simvastatin 10, 20, 40, or 80 mg (Merck & Co., Inc., Rahway, New Jersey); ezetimibe 10 mg plus simvastatin 10, 20, 40, or 80 mg; or placebo. Balanced randomization across treatment groups was accomplished using a single computer-generated randomization schedule with treatment codes in blocks of 10. Patients maintained the NCEP (or stricter) diet throughout the study and completed three-day diet diaries between prespecified visits. Diary entries were analyzed by Professional Nutrition Systems, Inc. (Overland Park, Kansas), the central diet analysis center.
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Figure 1 Study design. *Q1 = first qualifying LDL-C value using the Friedewald calculation; Q2 = second qualifying LDL-C value using the Friedewald calculation; blood samples for Q1 and Q2 were collected at least one week apart. Randomization to double-blind treatment occurred at Visit 4. NCEP = National Cholesterol Education Program.
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Blood samples for lipid measurements were collected at baseline and at Weeks 2, 4, 8, and 12; samples for high-density lipoprotein cholesterol (HDL-C) subfractions, apolipoproteins, and lipoprotein (a) were measured at baseline and Week 12. Evaluation of safety was accomplished through reports of patients, observations of investigators, and results of specific tests and measurements (laboratory tests, electrocardiograms, physical examinations, and vital signs).
Laboratory methods
Medical Research Laboratories (Highland Heights, Kentucky) performed all clinical laboratory analyses. Lipid results were blinded to the investigators and study sponsor beginning with the first qualifying lipid value. The LDL-C concentration was measured directly by ultracentrifugation (beta-quantification) and also calculated via the Friedewald equation (12): LDL-C = total cholesterol – (TG ÷ 5) – HDL-C. Total cholesterol (TC) and TG concentrations were quantified enzymatically with the Hitachi 747 analyzer (Roche Diagnostics Corporation, Indianapolis, Indiana). The HDL-C was determined enzymatically after LDL-C and very low-density lipoprotein cholesterol had been selectively removed by heparin and manganese chloride precipitation. The HDL3-C subfraction was quantified enzymatically after separation by ultracentrifugation, and the HDL2-C subfraction was calculated with the following equation: HDL2-C = HDL-C – HDL3-C. Apolipoprotein A-I and apolipoprotein B were determined by fixed-rate nephelometry. Lipoprotein (a) was quantified by competitive enzyme-linked immunosorbent assay. Non-HDL-C was calculated using the following equation: non-HDL-C = TC – HDL-C.
Statistical analysis
The primary efficacy variable was the percentage reduction in direct LDL-C from baseline to study end point (last postbaseline measurement) for the intent-to-treat population. The primary hypothesis was that the coadministration of ezetimibe 10 mg/day with simvastatin (pooled across all doses) would result in a significantly greater reduction in direct LDL-C when compared with simvastatin alone (pooled across all doses). The primary efficacy analysis was performed using a two-way analysis of variance model that extracted effects due to dose (simvastatin: 0, 10, 20, 40, and 80 mg), treatment (ezetimibe 10 mg and placebo), and treatment-by-dose interaction. The comparisons (pooled ezetimibe 10 mg plus simvastatin [10, 20, 40, 80 mg] group vs. pooled simvastatin [10, 20, 40, 80 mg] group and pooled ezetimibe 10 mg plus simvastatin [10, 20, 40, 80 mg] group vs. ezetimibe 10 mg group) were performed using contrast statements under the model to evaluate the primary hypothesis. Consistency of the treatment effect across subgroups (gender, age [<65 years, 65 years], race [white, non-white]), and treatment-by-factor (defining such subgroups) interactions were evaluated for the primary variable in the intent-to-treat population using analysis of variance models, including factors for treatment, dose, treatment-by-dose, subgroup, and treatment-by-subgroup interaction. With the planned sample size of approximately 650 patients (65 patients per treatment group), a difference between percentage reduction of directly measured LDL-C of any two individual treatment groups of 5 percentage points could be detected with 80% power and a significance level of p < 0.05 (two-tailed), assuming a standard deviation of 10.
Change from baseline to end point was also evaluated for the secondary lipid variables: calculated LDL-C, TC, TG, HDL-C, apolipoprotein B, non-HDL-C, HDL2-C, HDL3-C, apolipoprotein A-I, lipoprotein (a), and direct LDL-C:HDL-C and TC:HDL-C ratios. For evaluation of TG, a nonparametric evaluation using a one-way analysis of variance on the ranks extracting effect for treatment (10 groups) was performed to complement the parametric analysis. All statistical analyses were conducted using SAS software (version 8).
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Results
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Patient characteristics.
Of 2,645 individuals screened, 668 (25%) met the eligibility criteria and were randomized. Of the 668 patients, 591 (88%) completed the double-blind treatment phase, whereas 77 (12%) discontinued study treatment early because of an adverse event (42 patients), patient request (18 patients), noncompliance with protocol (13 patients), or loss to follow-up (4 patients). Of the 42 patients who discontinued study treatment early owing to an adverse event, 14 received simvastatin monotherapy (4 simvastatin 10 mg, 6 simvastatin 20 mg, 2 simvastatin 40 mg, 2 simvastatin 80 mg), 20 received coadministration therapy (2 ezetimibe plus simvastatin 10 mg, 7 ezetimibe plus simvastatin 20 mg, 3 ezetimibe plus simvastatin 40 mg, 8 ezetimibe plus simvastatin 80 mg), five received ezetimibe 10 mg monotherapy, and three received placebo. There was no pattern or trend across treatment groups in the distribution of patients who discontinued or in the reasons for discontinuation.
Demographics and baseline characteristics of the treatment groups were similar (Table 1). The intent-to-treat population consisted of 377 women and 291 men, 25 to 87 years of age, with hypercholesterolemia characterized by plasma concentrations of direct LDL-C from 137 to 247 mg/dl. Mean baseline plasma concentrations of direct LDL-C ranged from 174 to 182 mg/dl across treatment groups. Compliance data (mean percentages of total doses taken) ranged from approximately 90% to 97%.
Efficacy
Coadministration of ezetimibe plus simvastatin (pooled doses) was significantly more effective than simvastatin alone (pooled doses) in reducing plasma levels of direct LDL-C from baseline to end point, as evidenced by a mean percentage change of –49.9% for coadministration versus –36.1% for simvastatin alone (p < 0.01) (Table 2). Similarly, coadministration of ezetimibe plus simvastatin (pooled) was more efficacious than ezetimibe alone (mean percentage change in direct LDL-C from baseline to end point of –49.9% vs. –18.1%) (p < 0.01). Across the individual treatment groups, mean percentage changes in direct LDL-C from baseline to end point ranged from approximately –44% to –57% for coadministration versus –27% to –44% for simvastatin monotherapy (Fig. 2A). The incremental mean percentage change resulting from the coadministration of ezetimibe with each dose of simvastatin was statistically significant (p < 0.01) when compared with each corresponding dose of simvastatin monotherapy and between ezetimibe plus simvastatin 10 mg and both simvastatin 20 mg and simvastatin 40 mg alone, and between ezetimibe plus simvastatin 20 mg and simvastatin 40 mg alone. The mean percentage change in LDL-C achieved with ezetimibe plus simvastatin 10 mg was numerically similar to that with simvastatin 80 mg alone (approximately –44% in both cases). The incremental LDL-C-lowering effects resulting from the coadministration of ezetimibe with each dose of simvastatin were observed as early as Week 2 and maintained for the duration of the study (Fig. 3). The incremental reduction of LDL-C concentrations with coadministration of ezetimibe and simvastatin (all doses) was generally consistent across all subgroups tested, including risk-factor status, gender, age, race, or baseline lipid profile.
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Figure 2 Percentage change in direct low-density lipoprotein cholesterol (A), high-density lipoprotein cholesterol (B), and triglyceride (C) concentrations from baseline to end point. EZE = ezetimibe; Simva = simvastatin. Nonfilled columns = Simva; filled columns = Simva + EZE. In (A), the asterisk denotes p < 0.01, combination versus statin alone.
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Figure 3 Mean percent change from baseline in plasma concentration of direct low-density lipoprotein cholesterol (LDL-C) over time and at end point. EZE = ezetimibe; Simva = simvastatin.
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Results for calculated LDL-C were entirely consistent with those obtained for direct LDL-C. Individually, all coadministration treatment groups exhibited consistently greater mean percent changes in calculated LDL-C from baseline to end point (approximately –46%, –46%, –56%, and –58%, respectively) compared with simvastatin alone treatment groups (approximately –27%, –37%, –38%, and –45%). The difference between each dose of simvastatin plus ezetimibe 10 mg versus the same and the next higher dose of simvastatin alone was statistically significant (p < 0.01). As with direct LDL-C, coadministration of ezetimibe with simvastatin 10 mg resulted in a similar mean percent change as simvastatin 80 mg monotherapy (–46% and –45%, respectively).
Ezetimibe plus simvastatin (pooled) also significantly improved the following secondary efficacy variables compared with simvastatin alone (pooled) (Table 2): TG and TC, apolipoprotein B, non-HDL-C, direct LDL-C:HDL-C, and TC:HDL-C (p < 0.01); HDL-C (p = 0.03); and HDL3-C (p = 0.02). Figure 2 summarizes the changes in LDL-C, HDL-C, and TG concentrations across the individual treatment groups. Coadministration of ezetimibe with simvastatin compared with simvastatin alone significantly reduced direct LDL-C (Fig. 2A) at all simvastatin doses (p < 0.01), increased HDL-C at a simvastatin dose of 40 mg (Fig. 2B) (p = 0.02), and reduced TG (Fig. 2C) at simvastatin doses of 10 mg (p = 0.01) and 80 mg (p = 0.02).
Overall, 59% (157/268) of patients who received coadministration therapy compared with 15% (40/261) of patients who received simvastatin monotherapy achieved 50% reduction in plasma concentrations of direct LDL-C at end point. Based on the NCEP ATP III guidelines, 77% (207/268) of patients receiving coadministration therapy compared with 64% (167/261) of patients receiving simvastatin monotherapy had LDL-C concentrations above target levels at the start of treatment and below target at end point (Table 3). The differences between the two pooled treatment groups in the proportion of patients achieving either NCEP ATP II or ATP III target LDL-C concentrations were statistically significant (p < 0.01) (Table 3).
Safety
Treatment-emergent adverse events were reported for 72% of subjects on simvastatin monotherapy and 69% of subjects on coadministration therapy. The most common adverse events included upper respiratory tract infection (14% on simvastatin monotherapy vs. 15% on coadministration), headache (9% vs. 7%), and nausea (6% vs. 4%). Treatment-related adverse events were reported for 19% (50/263) of patients receiving simvastatin monotherapy and 20% (54/274) of patients receiving coadministration therapy (Table 4). Profiles for nonlaboratory-related adverse events were similar for the two pooled treatment groups. The types of adverse events resulting in treatment discontinuation (42/668, 5% of patients) or interruption (42/668, 5% of patients) were generally no more common or severe in any treatment group. Similar proportions of patients receiving coadministration therapy compared with simvastatin monotherapy reported significant adverse events resulting in discontinuation (7% [20/274] vs. 5% [14/263]) or interruption of study treatment (5% [15/274] vs. 7% [18/263]). One case of mild hepatomegaly and one case of severe cholelithiasis/cholecystectomy were reported. Both of these events occurred in patients receiving simvastatin monotherapy and were considered unlikely related to study medication.
One patient died postrandomization approximately one month after commencing study medication (ezetimibe plus simvastatin 20 mg) as a result of hypotension and respiratory failure secondary to a left middle cerebral artery infarction. The investigator considered the death to be unlikely related to study medication.
Patients were considered to have two consecutive postbaseline elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) if 1) there were two or more consecutive values 3x upper limit of normal (ULN); 2) the last value was 3x ULN; or 3) a measurement of 3x ULN during treatment or 2 days after the end of treatment was followed by a measurement <3x ULN that was taken >2 days after the last dose of study medication. Eight patients, six receiving coadministration therapy (1 ezetimibe plus simvastatin 20 mg, 4 ezetimibe plus simvastatin 40 mg, 1 ezetimibe plus simvastatin 80 mg) and two receiving simvastatin monotherapy (1 simvastatin 20 mg, 1 simvastatin 80 mg), had consecutive elevations 3x ULN for ALT and/or AST. Six patients of the eight cases, including five receiving coadministration therapy, had elevated ALT/AST levels at baseline (patients with elevations up to 2x ULN at baseline were allowed into the study), and four completed the study. All elevations in hepatic enzyme activity were asymptomatic, and no cases of hepatitis, jaundice, or signs of liver dysfunction were reported.
Two patients had clinically important elevations in creatine phosphokinase (CPK) activity. One patient in the simvastatin 20 mg group had signs and symptoms consistent with myopathy (defined as CPK 10x ULN with associated muscle symptoms). This patient reported mild myalgia ending five days before the CPK elevation and discontinuation of the study drug. A second patient, who was receiving simvastatin monotherapy (40 mg), had a 10x ULN increase in CPK activity (without associated muscle symptoms) that gradually declined while continuing the study drug. For these two patients, the investigator considered physical exercise a possible contributing factor to the increased CPK, which returned to the normal range after discontinuation of the study drug. Results of other laboratory tests, vital signs, electrocardiograms, and cardiopulmonary examinations did not suggest any clinically important differences between the coadministration and simvastatin monotherapy groups.
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Discussion
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Efficacy of coadministration of ezetimibe with simvastatin.
In this study, coadministration of ezetimibe plus simvastatin was more effective in reducing plasma concentrations of LDL-C than simvastatin or ezetimibe alone. Coadministration of ezetimibe with each dose of simvastatin resulted in a significant LDL-C-lowering effect compared with each corresponding dose of simvastatin alone (p < 0.01). Furthermore, the improvement was significantly greater than that seen with a doubling of the simvastatin dose alone. Coadministration of ezetimibe and simvastatin 10 mg resulted in a similar mean percentage change in LDL-C as simvastatin 80 mg alone. Thus, coadministration of ezetimibe with the lowest dose of simvastatin reduced LDL-C concentrations to a similar extent as increasing the simvastatin dose eightfold. A further enhancement of the LDL-C-lowering effect was obtained when ezetimibe was coadministered with simvastatin 80 mg, resulting in a mean percentage change from baseline of approximately –57% versus –44% with simvastatin 80 mg alone. The percentage reductions in plasma concentrations of LDL-C attained with the four doses of simvastatin administered in this study were consistent with those in the product labeling for simvastatin (15).
Favorable effects of simvastatin on lowering TC, TG, and apolipoprotein B concentrations and increasing HDL-C concentrations were all significantly enhanced by coadministration with ezetimibe. Moreover, the coadministration of ezetimibe and simvastatin significantly improved other risk factors for coronary heart disease such as LDL-C:HDL-C and TC:HDL-C ratios and non-HDL-C relative to simvastatin alone.
Results of pilot clinical pharmacology studies (10,11) suggesting that coadministration of ezetimibe and simvastatin would have an enhanced effect on LDL-C reduction have been confirmed in this larger Phase 3 study. In addition, in a similarly designed factorial study (16), coadministration of ezetimibe and atorvastatin provided significant incremental reductions in LDL-C (12.1%) and TG (8.0%) concentrations, as well as increases in HDL-C concentrations (3.0%) (p < 0.01) compared with atorvastatin alone. Therefore, the combination of the two different mechanisms of action of these agents (inhibition of cholesterol synthesis by simvastatin and inhibition of cholesterol absorption in the intestine by ezetimibe) results in a substantial incremental benefit in LDL-C as well as providing incremental beneficial effects on HDL-C and TG levels. The incremental LDL-C reduction obtained with the coadministration of a statin with ezetimibe provided significantly better LDL-C reductions compared with two doublings of the statin dose and similar results to a third doubling of the statin dose.
Safety of coadministration of ezetimibe with simvastatin
The overall safety profile of the coadministration therapy was generally similar to that of simvastatin alone and to placebo in this 12-week study. Generally, the adverse event profiles were similar across treatment groups. There was no evidence to suggest that the addition of ezetimibe to any dose of simvastatin increased the risk of any nonlaboratory adverse event. Furthermore, no pattern of a dose relationship was evident with respect to simvastatin, administered either alone or with ezetimibe.
Hepatobiliary function and CPK activity/myopathy were carefully evaluated in view of the known effects of lipid-lowering agents on these measures. Coadministration of ezetimibe with low doses of simvastatin (10 and 20 mg) produced similar or even greater LDL-C reductions compared with the highest simvastatin dose (80 mg) without altering the incidence of elevations in ALT/AST levels. Although five of the six increases with ezetimibe and simvastatin coadministration occurred in patients receiving simvastatin doses of 40 mg or higher, only one was seen in the ezetimibe plus simvastatin 80 mg group; the numbers were insufficient to confirm a clear dose relationship across the individual treatment groups. These asymptomatic increases in transaminase activities may be the result of a pharmacodynamic effect due to cholesterol reduction or alterations in hepatic metabolism (17–20). Except for sustained-release nicotinic acid, there is little evidence of hepatotoxicity with any of the lipid-lowering drugs (18,21,22).
The only CPK elevations 10x ULN occurred in the simvastatin monotherapy group. The observed occurrences of elevations in CPK activity and/or muscle-related adverse events did not suggest any new or clinically meaningful adverse effects of coadministration with ezetimibe beyond that already documented for simvastatin or statins in general. No cases of rhabdomyolysis were reported in this study.
Study limitations
Although the goal attainment analysis was exploratory, the results indicated that more patients were able to reach their LDL-C target with ezetimibe and simvastatin coadministration than with simvastatin therapy alone. This study was conducted while NCEP ATP II guidelines were in effect. Before the database was locked, new guidelines were established by ATP III; however, the patient data had been collected to characterize the patients according to the NCEP ATP II guidelines. Also, the trial was of fairly short duration (12 weeks), so analysis of long-term efficacy and safety is not possible.
Implications
The complementary mechanism of action of ezetimibe and simvastatin may offer a new multitargeted strategy for lipid management in patients with hypercholesterolemia. Coadministration of ezetimibe with low-dose simvastatin may be a well-tolerated treatment alternative to high-dose simvastatin monotherapy. In addition, coadministration of ezetimibe and simvastatin has the potential to increase the number of patients who can achieve the recommended target lipid levels. In clinical practice, ezetimibe may be coadministered with statins in patients who have been unable to achieve LDL-C target concentrations with statin monotherapy alone, as well as in patients at risk for increased side effects at higher doses of statin monotherapy. The need for less frequent statin dosage adjustments may lead to improved patient compliance and help more patients attain their LDL-C goals.
Conclusions
Coadministration of ezetimibe plus simvastatin 10, 20, 40, or 80 mg was more effective in reducing mean plasma concentrations of LDL-C than simvastatin or ezetimibe alone. A similar reduction in plasma concentrations of LDL-C was achieved with the coadministration of ezetimibe 10 mg plus simvastatin 10 mg as with simvastatin 80 mg alone. Reductions in the plasma concentrations of TC, TG, and apolipoprotein B and increases in the plasma concentrations of HDL-C were all significantly enhanced by the coadministration of ezetimibe plus simvastatin. The coadministration of ezetimibe plus simvastatin was well tolerated and had an overall safety profile similar to that of simvastatin alone and to placebo. Coadministration of ezetimibe and simvastatin offers a highly efficacious new treatment strategy for lipid-regulating therapy in patients with hypercholesterolemia (Appendix).
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APPENDIX
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Ezetimibe study group.
Writing Committee: Michael H. Davidson, MD, Thomas McGarry, MD, Robert Bettis, MD, Lorenzo Melani, MD, PhD, Leslie J. Lipka, MD, PhD, Alexandre P. LeBeaut, MD, Ramachandran Suresh, PhD, Steven Sun, PhD, and Enrico P. Veltri, MD.
Ezetimibe Study Group Investigators: Jeffrey M. Adelglass, MD, MDS Harris, Dallas, Texas; Pavan Kumar Anand, MD, The Center for Clinical Research, NCH Healthcare System, Naples, Florida; Janet Anderson, MD, and Denise R. Tonner, MD, Doctors’ Clinic, Vero Beach, Florida; Gregory P. Babikian, MD, Scripps Clinic, La Jolla, California; Mark Andrew Backus, MD, and Patrick H. Peters, Jr., MD, San Antonio, Texas; David J. Beccia, MD, Medical & Clinical Research Associates, LLC, Bay Shore, New York; W. Tyson Bennett, MD, Bennett Cardiac Center, Charlotte, North Carolina; Joan Ryder Benz, MD, PhD, Clinical Research, Cedar Rapids, Iowa; Sheldon Berger, MD, and Michael H. Davidson, MD, Chicago Center for Clinical Research, Chicago, Illinois; Robert Bettis, MD, Edmonds Family Medicine Clinic, Edmonds, Washington; Larry L. Carr, DO, Bay City, Michigan; Park T. Chittom, MD, Selma Doctors Clinic, Selma, Alabama; George Dailey III, MD, Scripps Clinic, La Jolla, California; Jeffrey O. Eastman, MD, Pacific Research Network, Sun City, California; Robert L. Feldman, MD, MedQuest Research Group, Inc., Ocala, Florida; James V. Felicetta, MD, Cart T. Hayden VAMC, Phoenix, Arizona; Stephen P. Glasser, MD, University of South Florida Cardiovascular Unit for Research & Education & Lipid Clinic, Tampa, Florida; Daniel Gottlieb, MD, Burien, Washington; Mitchell Greenspan, MD, Buxmont Cardiology Assoc, PC, Lifemark Medical Center, Sellersville, Pennsylvania; Lisa Harris, MD, The Chase Wellness Center, Virginia Beach, Virginia; Fred M. Heinemann, MD, Central Arkansas Cardiovascular Institute, PA, Hot Springs, Arkansas; Jeffrey R. Herbst, MD, and Andrew Ahmann, MD, Radiant Research, Inc., Portland, Oregon; Donald B. Hunninghake, MD, and Larry W. Kotek, MD, Heart Disease Prevention Clinic, Minneapolis, Minnesota; Robert H. Hutchins, MD, New Hanover Medical Research, Wilmington, North Carolina; Spencer B. Jones, MD, Radiant Research Inc., Salt Lake City, Utah; Steven L. Kanner, DO, Radiant Research, Inc., West Palm Beach, Florida; James R. Kelly, MD, Durham Internal Medicine, Durham, North Carolina; Douglas P. Lyle, MD, Anaheim Heart & Research Institute, Laguna Hills, California; Thomas C. Marbury, MD, Orlando Clinic Research Center, Orlando, Florida; Orlando H. Maytin, MD, Renstar Medical Research, Plantation, Florida; Thomas F. McGarry, MD, Oklahoma Foundation for Cardiovascular Research, Oklahoma City, Oklahoma; Clark D. McKeever, MD, Health Advance Institute, Houston, Texas; Paul B. Moore, MD, Radiant Research, Inc., Austin, Texas; David J. Morin, MD, TriCities Medical Research Associates, Bristol, Tennessee; John V. Murray, Jr., MD, Radiant Research, Inc., St. Petersburg, Florida; John P. Nardandrea, MD, Renstar Medical Research, Ocala, Florida; Diane M. Normandin, MD, Clinical Research of West Florida, Clearwater, Florida; Suzanne Oparil, MD, The University of Alabama at Birmingham, Birmingham, Alabama; Richard M. Pavelock, MD, Carolina Primary & Urgent Care, Statesville, North Carolina; Ana Y. Perez, MD, Pro-Research Group, LLC, San Antonio, Texas; Peter Philander, MD, Pharmacology Research Clinic, Las Vegas, Nevada; Beverly Elizabeth Phillipson, MD, and Douglas Lee Dawley, MD, The Oregon Clinic, Portland, Oregon; Guy N. Piegari, Jr., MD, Berks Cardiologists, Reading, Pennsylvania; R. Prasad Potu, MD, The Florida Wellcare Alliance, Inverness, Florida; Albert J. Razzetti, University Clinic Research, DeLand, Florida; Michele Reynolds, MD, Radiant Research, Inc., Dallas, Texas; Mark W. Riederman, MD, Deerpath Medical Associates, Inc., Lake Bluff, Illinois; Owen Lee Robinson, MD, Western Clinic Research, Inc., Torrance, California; David Rodriguez, MD, Georgia Research Associates, Atlanta, Georgia; John Rubino, MD, Raleigh Medical Group, Raleigh, North Carolina; Randall J. Severance, MD, Mesa Center for Clinical Research, Mesa, Arizona; Gerald Shockey, MD, Clinic of Physicians and Surgeons, Ltd., Mesa, Arizona; Katherine L. Smallwood, MD, Virginia Physicians, Inc., Richmond, Virginia; Eric Stephen Solomon, MD, Riverchase Clinical Research, PC, Pelham, Alabama; Jacques G. Susset, MD, MultiMed Research, Providence, Rhode Island; Martin L. Throne, Radiant Research, Inc., Atlanta, Georgia; Robert J. Weis, MD, Androscoggin Cardiology Associates, Auburn, Maine; Thaddeus Wilczewski, MD, and Piotr Slaski, PharmaTrials, Inc., Brooklyn, New York; Gerald D. Wolfley, MD, Radiant Research, Inc., Scottsdale, Arizona; Diana L. Wright, MD, Iowa Diabetes & Endocrinology Center, Des Moines, Iowa; Edward T. Zawada, Jr., MD, USD Internal Medicine Clinical Research, Sioux Falls, South Dakota.
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Acknowledgments
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We thank Arlene Reiss for her assistance in the preparation of this manuscript.
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Footnotes
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This study was conducted by Schering-Plough Research Institute, Kenilworth, New Jersey, on behalf of Merck/Schering-Plough Pharmaceuticals, North Wales, Pennsylvania.
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