Long-term up to 24-month efficacy and safety of concomitant prescription omega-3-acid ethyl esters and simvastatin in hypertriglyceridemic patients

Abstract

Objective:

Assess the long-term efficacy and safety of prescription omega-3-acid ethyl esters (P-OM3) coadministered with simvastatin in an extension of the Combination of Prescription Omega-3 Plus Simvastatin (COMBOS) trial.

Methods:

COMBOS included hypertriglyceridemic patients (triglyceride [TG] ≥200 mg/dL and <500 mg/dL or ≥2.26 mmol/L and <5.64 mmol/L) with low density lipoprotein cholesterol (LDL-C) level no greater than 10% above the National Cholesterol Education Program, Adult Treatment Panel III treatment goal. After an 8-week lead-in phase with simvastatin 40 mg/day (which continued throughout the trial), subjects were randomized to 8 weeks of P-OM3 4 g/day or placebo. Completers were eligible to participate in a 24-month extension study. Those who received placebo + simvastatin in COMBOS switched to open-label P-OM3 + simvastatin (‘Switchers’); those who received P-OM3 + simvastatin during COMBOS continued the same regimen (open-label) in the extension phase (‘Non-switchers’). The primary endpoint was the difference between Non-switchers and Switchers in median percent change in non-high-density lipoprotein-cholesterol (non-HDL-C) from COMBOS end of treatment to Month 4 of the extension phase.

Results:

At Month 4 from COMBOS end of treatment, non-HDL-C was reduced by a median of 9.4% in Switchers and increased by 0.9% in Non-switchers (p < 0.001). For the total population (combined Non-switcher + Switcher population), the median percent change from COMBOS baseline to Months 4, 12, and 24 was −8.3%, −7.3%, and −8.9%, respectively (all p < 0.001). This extension study revealed no unexpected safety findings. A limitation of this study was a gap between completion of COMBOS and enrollment in the extension phase for some patients; however, a post-hoc non-HDL-C sensitivity analysis performed at the 4-month primary endpoint revealed no influence of gap on study results.

Conclusions:

In this 24-month extension study, P-OM3 was generally well tolerated, and produced sustained reductions in non-HDL-C levels in simvastatin-treated patients with TG levels between 200 and 500 mg/dL (2.26 mmol/L and 5.64 mmol/L).

Clinical Trial Registry Number:

NCT00903409.

Key words::

• Hypertriglyceridemia
• Non-HDL-C
• Prescription omega-3-acid ethyl esters
• Simvastatin

Transparency

Declaration of funding

Funding for this study was provided by GlaxoSmithKline, NCT00903409.

Declaration of financial/other relationships

H.E.B. has disclosed that he has served as a clinical investigator; has received research grants; and has received consultant, advisor and speaker payments from numerous pharmaceutical companies, including Reliant and GlaxoSmithKline. K.C.M. has disclosed that he has received research grant support as well as consulting fees and honoraria from GlaxoSmithKline and Reliant. J.M. has disclosed that he has served as a consultant for Abbott Laboratories, Agerion, AstraZeneca, GlaxoSmithKline, Merck & Co, and Daiichi Sankyo. R.S., A.M. and R.S. have disclosed that they are current employees of GlaxoSmithKline. R.T.D. has disclosed that he is a former employee of Reliant Pharmaceuticals, Inc., and currently a clinical consultant for GlaxoSmithKline. E.S. has disclosed that he has received grants, consulting fees and honoraria, and/or has delivered lectures for AACC, Abbott, AstraZeneca, FDA, F. Hoffmann-La Roche Ltd, ISIS, Merck & Co, NLA Novartis, Reliant, Sankyo, sanofi-aventis, Schering-Plough, Takeda and Wyeth. R.S., A.M. and R.S. have disclosed that they are employees of GlaxoSmithKline and that they contributed to this paper by analyzing and interpreting the study data and by critically revising the manuscript for important intellectual content. R.T.D. has disclosed that he is a former employee of Reliant Pharmaceuticals, Inc., and currently a clinical consultant for GlaxoSmithKline. He has disclosed that he contributed by helping design the study, by analyzing and interpreting the study data, and by critically revising the manuscript for important intellectual content.

Some peer reviewers receive honoraria from CMRO for their review work. The peer reviewers of this paper have disclosed that they have no relevant financial relationships.

Acknowledgment

Editorial support in the form of developing a draft outline and a manuscript first draft was provided by Kevin Jarvis, PharmD, from BioCentric, Inc., and was funded by GlaxoSmithKline. The authors acknowledge Doug Wicks, MPH, for his contributions to the draft development and critical review of this manuscript.

All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors and assume responsibility for the direction and content.

Notes

*Lovaza is a registered trademark of Reliant Pharmaceuticals, Inc., a member of the GlaxoSmithKline group of companies.