Original Article
Efficacy and Safety of Ezetimibe Coadministered With Simvastatin in Patients With Primary Hypercholesterolemia: A Randomized, Double-Blind, Placebo-Controlled Trial

https://doi.org/10.4065/79.5.620Get rights and content

Objective

To compare the efficacy and safety of 10 mg of ezetimibe coadministered with simvastatin with the safety and efficacy of simvastatin monotherapy for patients with hypercholesterolemia.

Patients and Methods

This multicenter double-blind, placebo-controlled, factorial study enrolled 887 patients with hypercholesterolemia (low-density lipoprotein cholesterol [LDL-C], 145-250 mg/dL; triglycerides, ≤350 mg/dL). Patients were randomized to 1 of 10 treatments— placebo, ezetimibe at 10 mg/d, simvastatin at 10, 20, 40, or 80 mg/d, or simvastatin at 10, 20, 40, or 80 mg/d plus ezetimibe at 10 mg/d for 12 weeks. The study began March 13, 2001, and ended January 8, 2002. The primary efficacy end point was the mean percent change in LDL-C levels from baseline to study end point (last available postbaseline LDL-C measurement) for the pooled ezetimibe/simvastatin group vs the pooled simvastatin monotherapy group.

Results

Coadministration of ezetimibe/simvastatin was significantly (P<.001) more effective than simvastatin alone in reducing LDL-C levels for the pooled ezetimibe/simvastatin vs pooled simvastatin analysis and at each specific dose comparison. The decrease in LDL-C levels with coadministration of ezetimibe and the lowest dose of simvastatin, 10 mg, was similar to the decrease with the maximum dose of simvastatin, 80 mg. A significantly (P<.001) greater proportion of patients in the ezetimibe/simvastatin group achieved target LDL-C levels compared with those in the monotherapy group. Treatment with ezetimibe/simvastatin also led to greater reductions in total cholesterol, triglyceride, non-high-density lipoprotein cholesterol, and apolipoprotein B levels compared with simvastatin alone; both treatments increased high-density lipoprotein cholesterol levels similarly. The safety and tolerability profiles for the ezetimibe/simvastatin and monotherapy groups were similar.

Conclusion

Through dual inhibition of cholesterol absorption and synthesis, coadministration of ezetimibe/simvastatin offers a highly efficacious and well-tolerated lipid-lowering strategy for treating patients with primary hypercholesterolemia.

Section snippets

Selection Criteria

Each patient gave written informed consent to participate in this study. Eligible patients were men and women aged 18 years or older with primary hypercholesterolemia (LDL-C, 145-250 mg/dL; TG, ≤350 mg/dL), liver transaminase levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) no more than 2 times the upper limit of normal with no active liver disease, and creatine kinase (CK) level no more than 1.5 times the upper limit of normal.

Exclusionary concomitant conditions and

Demographics, Baseline Characteristics, and Patient Accounting

The treatment groups were well balanced with respect to demographics and baseline characteristics (Table 1). The ITT population consisted of 887 patients: 473 women and 414 men, aged 22 to 81 years, with mean baseline LDL-C plasma concentrations ranging from 174 to 176 mg/dL across treatment groups. Of the 887 randomized patients, 813 patients completed the study (Figure 1). Seventy-four patients discontinued treatment because of consent withdrawn (n=31), adverse events (n=28), lost to

DISCUSSION

Because blood cholesterol levels are maintained through both endogenous synthesis and intestinal absorption, our hypothesis was that a treatment strategy that affects these 2 sources would be more effective than a strategy that affects only 1. The results of our study confirm those of an earlier study14 and support the hypothesis that coadministration of ezetimibe/simvastatin, working through dual inhibition of cholesterol synthesis and absorption, is more efficacious than simvastatin

CONCLUSION

This study showed that coadministration of ezetimibe/simvastatin, a treatment strategy that targets both synthesis and intestinal absorption of cholesterol, had greater lipidlowering efficacy than simvastatin monotherapy, as well as a similar overall safety profile. Thus, coadministration of ezetimibe/simvastatin is a highly efficacious and well-tolerated treatment for improving lipid profiles in patients with hypercholesterolemia.

Ezetimibe Study Group.—Harold Bays, MD, L-MARC Research Center,

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This study was sponsored by Merck/Schering-Plough Pharmaceuticals, North Wales, Pa. Drs Sapre and Mitchel and Ms Liu and Ms Capece are employees of Merck & Co, Inc, and own stock in Merck & Co, Inc.

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