Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia

doi:10.1016/S0002-9149(02)02774-1

The American Journal of Cardiology

Volume 90, Issue 10, 15 November 2002, Pages 1084-1091

https://doi.org/10.1016/S0002-9149(02)02774-1 Get rights and content

Abstract

Ezetimibe is a lipid-lowering drug that inhibits the intestinal absorption of dietary and biliary cholesterol by blocking passage across the intestinal wall. The efficacy and safety of adding ezetimibe to ongoing statin therapy in patients with primary hypercholesterolemia was evaluated in a randomized, double-blind, placebo-controlled study. The study group included 769 adults (aged ≥18 years) with primary hypercholesterolemia who had not achieved National Cholesterol Education Program (NCEP) Adult Treatment Panel II goals with dietary alteration and statin monotherapy. Patients receiving a stable dose of a statin for ≥6 weeks were randomized to receive concurrent treatment with placebo (n = 390) or ezetimibe (n = 379), 10 mg/day, in addition to continuing their open-label statin for 8 weeks. The primary efficacy variable was the percent change in low-density lipoprotein (LDL) cholesterol from baseline with statin monotherapy to end point after intervention (secondary variables: high-density lipoprotein [HDL] cholesterol and triglycerides). Ongoing statin therapy plus ezetimibe led to changes of −25.1% for LDL cholesterol (HDL cholesterol +2.7%; triglycerides −14.0%) compared with LDL cholesterol −3.7% (p <0.001), HDL cholesterol +1.0% (p <0.05), and triglycerides −2.9% (p <0.001) for placebo added to ongoing statin therapy. Among patients not at LDL cholesterol goal at on-statin baseline, 71.5% receiving statin plus ezetimibe versus 18.9% receiving statin plus placebo reached goal at end point (odds ratio 23.7; p <0.001). The co-administration of statin and ezetimibe was generally well tolerated. Adding ezetimibe to ongoing statin therapy led to substantial additional reduction in LDL cholesterol levels, facilitating attainment of NCEP goals. Ezetimibe offers a new therapeutic option for patients receiving statins who require further reduction in LDL cholesterol.

Section snippets

Study population:

Prospective patients with primary hypercholesterolemia were provided information about the trial, had questions answered, and signed an informed consent. The patient population consisted of adults ≥18 years of age, currently taking a stable daily dose of a statin for ≥6 weeks. Patients must have been previously instructed on a cholesterol-lowering diet. Each patient’s mean LDL cholesterol level, calculated from 2 separate determinations during screening (visits 1 and 2), had to be at or above

Demographic and baseline characteristics and patient disposition:

Between December 2000 and April 2001, 769 patients taking statin monotherapy were randomized to treatment with either the addition of ezetimibe 10 mg/day (n = 379) or matching placebo (n = 390) at 80 study centers (51 United States centers, 29 international). Patient demographics and baseline characteristics are listed in Table 1. Treatment groups were generally balanced with respect to age, gender, race, diet, weight, and body mass index. Approximately 68% of patients had coronary heart

Discussion

The objective of the present study was to evaluate the efficacy and safety of ezetimibe when added to ongoing statin therapy in a population of patients at high cardiovascular risk who had not achieved their recommended LDL cholesterol goal. The results indicate that a clinically meaningful reduction in LDL cholesterol occurs when ezetimibe is added to ongoing statin therapy. Moreover, this reduction is associated with achievement of the treatment goal in a substantial number of patients not

Acknowledgements

We wish to thank Arlene Reiss, BS, and Ken Youngren, PhD, for assisting in the preparation of this manuscript.

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Ezetimibe is an azetidinone derivative and a substituted β‐lactam, it is a hypolipidemic agent, and a drug substance that lowers the cholesterol levels in our body. The present work describes the origin, synthesis, and characterization of three impurities of ezetimibe, which are also positional isomers and/or related substances of ezetimibe. viz: o‐Fluoro benzene isomer, m‐Fluoro aniline analog, and des‐fluoro aniline analogs of ezetimibe.
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Effects of Fixed-dose Combination of Low-intensity Rosuvastatin and Ezetimibe Versus Moderate-intensity Rosuvastatin Monotherapy on Lipid Profiles in Patients With Hypercholesterolemia: A Randomized, Double-blind, Multicenter, Phase III Study
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We investigated whether the combination therapy of low-intensity rosuvastatin and ezetimibe is an useful alternative to moderate-intensity rosuvastatin monotherapy in patients requiring cholesterol-lowering therapy.
This was a multicenter randomized, double‐blind study to investigate the safety and efficacy of a fixed-dose combination of rosuvastatin 2.5 mg and ezetimibe 10 mg (R2.5+E10) compared to those of ezetimibe 10 mg monotherapy (E10), rosuvastatin 2.5 mg (R2.5), and rosuvastatin 5 mg monotherapy (R5) in patients with hypercholesterolemia. A total of 348 patients at 15 centers in Korea were screened, and 279 patients were randomized to different groups in the study. Clinical and laboratory examinations were performed at baseline and 4 and 8 weeks after intervention. The primary endpoint was the percentage change of low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up.
Baseline characteristics were similar among the four groups. There were significant changes in lipid profiles at the 8-week follow-up. A greater decrease in the LDL cholesterol levels (primary endpoint) were found in the R2.5+E10 group (−45.7±18.6%) than in the E10 group (−16.7±14.7%, p<0.0001), R2.5 group (−32.6±15.1%, p<0.0001), and R5 group (−38.9±13.9%, p=0.0003). Similar outcomes were observed regarding the decrease in total cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B protein. In addition, changes in the triglyceride and HDL levels in the R2.5+E10 group were significantly different compared with those in the E10 group; however, the changes were similar to those in the other treatment groups. In patients with low and moderate risk, all patients achieved the target LDL cholesterol levels in the R2.5+E10 group (100%) compared to 13.0% in the E10 group, 47.6% in the R2.5 group, and 65.2% in the R5 group. Adverse effects were rare and similar in the four groups.
Fixed-dose combination of low-intensity rosuvastatin and ezetimibe was more effective in lowering LDL cholesterol and achieving LDL cholesterol goals than moderate-intensity rosuvastatin monotherapy. These findings suggest that the combination therapy of low-intensity rosuvastatin and ezetimibe is an useful alternative to moderate-intensity rosuvastatin monotherapy for cholesterol management, particularly in patients with low and moderate risk. ClinicalTrials.gov identifier: NCT04652349.
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A database search of PubMed and ClinicalTrials.gov was conducted for articles published between January 2012 to September 2020 and containing the key words bempedoic acid, ezetimibe, Nexletol and Nexlizet. Trials from the CLEAR series were selected, as they played a pivotal role in the establishment of FDA approval, along with additional trials published after FDA approval, which provided novel evidence on the use of bempedoic acid in the treatment of hypercholesterolemia. Publications that were not randomized, controlled trials were not included in this review. Only randomized controlled trials in which ezetimibe was used in conjunction with bempedoic acid were included in this review as they were relevant to the new FDA approval of bempedoic acid.
The findings of the present review show that bempedoic acid is both an effective and well-tolerated option for the treatment of hypercholesterolemia when used without ezetimibe in addition to standard therapy. It also appears that the combination with ezetimibe increases the cholesterol-lowering effect more than either agent alone when added to standard therapy.
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^☆: This trial was funded by MSP Singapore Company, LLC, a joint venture between Schering Corporation and Merck & Co., North Wales, Pennsylvania.

^*: A complete list of participants appears in the Appendix.

View full text

Regular paperEfficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia☆

Abstract

Section snippets

Study population:

Demographic and baseline characteristics and patient disposition:

Discussion

Acknowledgements

Atherosclerosis

Atherosclerosis

Atherosclerosis

Atherosclerosis

In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey through the identification of the active metabolites of SCH48461

J Pharmacol Exp Ther

Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663

Br J Pharmacol

Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function

Br J Pharmacol

The effect of gender on the pharmacokinetics of SCH 58235, a cholesterol absorption inhibitor (abstr)

Effect of SCH 58235 on the activity of drug metabolizing enzymes in vivo

Clin Pharmacol Ther

Ezetimibe does not affect the pharmacokinetics or pharmacodynamics of warfarin

Clin Pharmacol Ther

Ezetimibe does not affect the pharmacokinetics and pharmacodynamics of glipizide

Clin Pharmacol Ther

Ezetimibe does not affect the pharmacokinetics of oral contraceptives

Clin Pharmacol Ther

zetimibe does not alter the pharmacokinetics and pharmacodynamics of digoxin (abstr)

Regular paper
Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia☆