Elsevier

Journal of Clinical Lipidology

Volume 6, Issue 6, November–December 2012, Pages 565-572
Journal of Clinical Lipidology

Original Article
Icosapent ethyl, a pure EPA omega-3 fatty acid: Effects on lipoprotein particle concentration and size in patients with very high triglyceride levels (the MARINE study)

https://doi.org/10.1016/j.jacl.2012.07.001Get rights and content

Background

Icosapent ethyl (IPE; formerly AMR101) is a high-purity prescription form of eicosapentaenoic acid ethyl ester. In the MARINE study we evaluated the efficacy and safety of IPE in patients with very high triglycerides (TG; ≥500 mg/dL) and previously demonstrated significant reductions in TG levels with no significant increases in low-density lipoprotein (LDL) cholesterol levels.

Objectives

In this follow-up, exploratory analysis, we report the effects of IPE on lipoprotein particle concentration and size.

Methods

MARINE was a phase 3, multicenter, placebo-controlled, randomized, double-blind, 12-week study. Hypertriglyceridemic patients (N = 229) were randomized to three treatment groups: IPE 4 g/day, IPE 2 g/day, or placebo. Lipoprotein particle concentrations and sizes were measured by nuclear magnetic resonance spectroscopy.

Results

Compared with placebo, IPE 4 g/day significantly reduced median concentrations of large very-low-density lipoprotein (VLDL; −27.9%; P = .0211), total LDL (−16.3%; P = .0006), small LDL (−25.6%; P < .0001), and total high-density lipoprotein (HDL; −7.4%; P = .0063) particles and reduced VLDL particle size (−8.6%; P = .0017). In this patient population with TG ≥500 mg/dL, IPE did not significantly change the overall sizes of LDL or HDL particles.

Conclusion

IPE 4 g/day significantly reduced large VLDL, total LDL, small LDL, and total HDL particle concentrations and VLDL particle size in patients with TG ≥500 mg/dL. Changes in VLDL particle concentration and size reflect the TG-lowering effects of eicosapentaenoic acid. The reduction in LDL particle concentration with IPE is novel among ω-3 therapies and is consistent with the previously reported reduction in apolipoprotein B and lack of LDL-C increase with IPE in patients with very high TG levels.

Clinical trial registration number: NCT01047683.

Introduction

Hypertriglyceridemia is directly associated with an increased risk of atherosclerotic coronary heart disease (CHD).1 Consumption of the marine ω-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lowers triglyceride (TG) plasma levels.2 However, TG-lowering therapies containing both EPA and DHA may increase low-density lipoprotein (LDL) cholesterol, especially in patients with marked elevations of TGs at baseline.3 In previous smaller studies of patients with normal to moderately elevated TG levels, purified EPA reduced TG levels without increasing LDL cholesterol levels.4, 5, 6, 7, 8, 9

Icosapent ethyl (IPE; Vascepa® [formerly AMR101]; Amarin, Bedminster, NJ) is a high-purity prescription form of EPA ethyl ester approved by the United States Food and Drug Administration as an adjunct to diet to reduce TG levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. The MARINE study (Multi-Center, PlAcebo-Controlled, Randomized, Double-BlINd, 12-week study with an open-label Extension)10 was the largest clinical trial of any ω-3 fatty acid agent in this particular patient population (N = 229) in which investigators evaluated the efficacy and safety of IPE in patients with very high TG levels (≥500 mg/dL and ≤2000 mg/dL). In this study, IPE significantly reduced TG levels (IPE 4 g/day: −33.1%; P < .0001) without increasing LDL cholesterol levels.10 Among those with baseline TG levels >750 mg/dL, IPE 4 g/day reduced the placebo-adjusted TG levels by 45.4% (mean baseline TG level, 902.0 mg/dL; P = .0001).

LDL cholesterol is the primary treatment target for cholesterol-lowering therapy for prevention of CHD.11 It is the consensus of many lipidologists that apolipoprotein B and lipoprotein particle concentration are also important factors influencing atherogenicity, as well as being potentially useful in the initial assessment and on-treatment lipid management of hypertriglyceridemic patients at increased CHD risk.12 This exploratory analysis reports the effects of IPE on lipoprotein particle concentrations and sizes in patients with baseline TG levels ≥500 mg/dL.

Section snippets

Methods

MARINE was a phase 3, multicenter, placebo-controlled, randomized, double-blind, 12-week study that evaluated the efficacy and safety of IPE in patients with very high TG levels (≥500 mg/dL and ≤2000 mg/dL). Details of the MARINE study design and methods were reported elsewhere.10 In summary, following a 4- to 6-week lead-in period of diet, lifestyle, medication stabilization, and washout of prohibited lipid-altering medication, patients aged >18 years of age entered a 2- to 3-week

Results

In total, 224 patients were included in the ITT population of the MARINE study; 177 of these had evaluable samples for lipoprotein particle analysis with 61, 63, and 53 patients in the IPE 4 g/day, IPE 2 g/day, and placebo groups, respectively. The analysis of LDL particle size contained 60 patients in the IPE 4 g/day group. Baseline demographics were comparable among treatment groups (Table 1) and were similar to those reported for the overall randomized MARINE population.10 The majority of

Discussion

This exploratory analysis of the MARINE study was the largest of any ω-3 fatty acid study to report lipoprotein particle data for patients with very high TG (≥500 mg/dL) and was conducted to examine the effects of IPE, a high-purity prescription form of EPA ethyl ester, on lipoprotein particle concentrations and sizes. In this analysis, IPE 4 g/day significantly reduced the particle concentrations of large VLDL by 27.9%, total LDL by 16.3%, small LDL by 25.6%, and total HDL by 7.4% compared

Conclusions

In this 12-week study of patients with TG levels ≥500 and ≤2000 mg/dL, IPE 4 g/day significantly reduced large VLDL, total LDL, small LDL, and total HDL particle concentrations and VLDL particle size. The reduction in LDL particle concentration observed with IPE therapy is novel among ω-3 therapies and is consistent with the previously reported reduction in apolipoprotein B concentration and lack of LDL cholesterol concentration increase in patients with very high TG levels treated with IPE.

Financial disclosures

The MARINE study was sponsored and designed by Amarin Pharma Inc., Bedminster, New Jersey, and conducted by Medpace Reference Laboratories, Cincinnati, Ohio, with funding from Amarin Pharma Inc. Editorial assistance was provided by Peloton Advantage, LLC, Parsippany, New Jersey, and funded by Amarin Pharma Inc. In the past year, Dr. Bays' affiliated research site has received research grants from Amarin Pharma Inc., Amgen, Boehringer Ingelheim, Essentialis, Forest, Gilead, GlaxoSmithKline,

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