Long-term (48-week) safety of ezetimibe 10 mg/day coadministered with simvastatin compared to simvastatin alone in patients with primary hypercholesterolemia^*

ABSTRACT

Objective: This study evaluated the long-term safety and tolerability of ezetimibe/simvastatin coadministration therapy compared to simvastatin monotherapy in patients with primary hypercholesterolemia.

Research design and methods: After completing a 12-week randomized, double-blind, placebo-controlled, factorial, 10-armed study comparing ezetimibe 10 mg/simvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg; or placebo, 768 patients entered a 48-week extension, with randomized, blinded, reassignment of the simvastatin 10 mg, ezetimibe, and placebo groups to one of the ezetimibe/simvastatin groups. Patients previously receiving ezetimibe/simvastatin combination therapy, or simvastatin 20, 40, and 80 mg monotherapy continued the same therapies in this 7-arm extension study. During the extension study, investigators assessed adverse events (AEs).

Main outcome measures and results: Ezetimibe/simvastatin (n = 539) and simvastatin monotherapy (n = 229) groups generally had a similar incidence of all clinical AEs (73 vs. 69%), treatment-related AEs (14 vs. 11%), clinical serious AEs (SAE) (5.2 vs. 2.6%), treatment-related SAEs (0.2 vs. 0%), discontinuations due to all clinical AEs (4.5 vs. 2.6%) and discontinuations due to treatment-related AEs (2.8 vs. 2.2%), respectively. The incidence of total laboratory-related AEs for the ezetimibe/simvastatin and simvastatin monotherapy groups was also similar (12.2 vs. 11.9%), as was treatment-related laboratory AEs (6.2 vs. 5.3%), laboratory SAEs (0 vs. 0%), treatment-related laboratory SAEs (0 vs. 0%), discontinuations due to laboratory AEs (3.0 vs. 0.9%) and discontinuations due to treatment-related laboratory AEs (3.0 vs. 0.4%), respectively. There were no cases of myopathy, rhabdomyolysis, or serious hepatotoxicity observed in any group during this extension study.

Conclusions: During this 48-week extension study, the coadministration of ezetimibe/simvastatin was generally as well tolerated as simvastatin monotherapy. The direct application of study observations to clinical practice is limited by patient selection criteria and dosage regime, which randomly applied relatively high doses rather than titration which often occurs in clinical practice.

Key words: :

• Ezetimibe
• Ezetimibe-simvastatin combination
• Hypercholesterolemia
• Safety
• Simvastatin
• Statin

Acknowledgements

Declaration of interest: This study was funded by Merck/Schering-Plough Pharmaceuticals, North Wales, PA. HB received grant support from Merck Research Laboratories for conduct of clinical phases of the study, and is a member of the Merck Speakers bureau. AS, WT, JL, RC, and AT are employees of Merck Research Laboratories and own stock and/or hold stock options in the Company. The authors acknowledge the efforts of Jennifer Rotonda PhD, who is an employee of Merck Research Laboratories and owns stock and/or holds stock options in the company, for the data presentation and editorial review.

Notes

* The hsCRP data presented in this paper were combined with data from another study and submitted as an abstract and presented as a poster at the 2003 American Heart Association national meeting, November 9–12, 2003 in Orlando, FL, USA