Icosapent Ethyl Effects on Fatty Acid Profiles in Statin-Treated Patients With High Triglycerides: The Randomized, Placebo-controlled ANCHOR Study.

INTRODUCTION: Fatty acid content in plasma and red blood cells (RBCs) may provide insight into potential physiologic benefits of omega-3 fatty acids. Icosapent ethyl is a pure prescription form of eicosapentaenoic acid (EPA) ethyl ester approved by the US Food and Drug Administration at a dose of 4 g/day as an adjunct to diet to reduce triglyceride levels in adults with severe (≥ 500 mg/dl) hypertriglyceridemia. METHODS: This was a prespecified exploratory subset analysis of the ANCHOR study, which randomized 702 statin-treated patients at increased cardiovascular risk with triglycerides 200-499 mg/dl and controlled low-density lipoprotein cholesterol (40-99 mg/dl). This analysis examined effects of icosapent ethyl 4 g/day versus placebo on fatty acid levels in plasma and RBCs using a gas chromatograph assay method with flame ionization detector. RESULTS: In plasma, treatment with icosapent ethyl 4 g/day resulted in significant increases versus placebo in the mean concentrations of EPA (+ 635%; P < 0.0001) and its metabolite, docosapentaenoic acid n-3 (+ 143%; P < 0.0001) with no significant change in docosahexaenoic acid. Treatment with icosapent ethyl 4 g/day versus placebo also resulted in significant decreases in the omega-6 fatty acids linoleic acid (- 25%) and arachidonic acid (AA; - 31%), as well as the AA/EPA ratio (- 91%). Icosapent ethyl 4 g/day also decreased the omega-9 fatty acid oleic acid (- 29%) and the saturated fatty acids palmitic acid (- 23%) and stearic acid (- 16%) (all P < 0.0001). Results were similar for RBCs. CONCLUSIONS: Icosapent ethyl 4 g/day significantly increased EPA and produced other potentially beneficial shifts in fatty acids in plasma and RBCs versus placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT01047501 FUNDING: Amarin Pharma Inc. Plain language summary available for this article.

Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on plasma and red blood cell fatty acids in patients with very high triglyceride levels (results from the MARINE study).

INTRODUCTION: Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester. We evaluated IPE's effects on plasma and red blood cell (RBC) fatty acids (FA) and the relationship to triglyceride (TG) lowering. MATERIALS AND METHODS: This was a predefined, exploratory analysis (N=229) of FA plasma concentration and RBC membrane content from the double-blind, placebo-controlled MARINE study. RESULTS: Mean placebo-adjusted plasma EPA levels increased from baseline by 792% and 402% and the arachidonic acid/EPA plasma ratio decreased from baseline by 99% and 88% with IPE 4 g/day and 2 g/day, respectively (all P<.0001). Overall, the fractional pool of omega-3 FAs increased; there was a decrease or no change for omega-6 FAs. The increase in EPA levels with increased IPE dose corresponded with the TG-lowering effect. Similar FA shifts were observed in RBCs. CONCLUSIONS: IPE significantly increased plasma and RBC FAs, which correlated to TG lowering.

Long-chain polyunsaturated fatty acids modulate interleukin-1beta-induced changes in behavior, monoaminergic neurotransmitters, and brain inflammation in rats.

Recent evidence has suggested that an imbalance between membrane (n-3) and (n-6) fatty acids may contribute to the etiology of autoimmune and neurodegenerative diseases. In this study, the mechanisms by which eicosapentaenoic acid (EPA), gamma-linolenic acid (GLA), and arachidonic acid (AA) modulate neurotransmitters, behavior, and brain inflammation were evaluated in rats that received central saline or interleukin-1beta (IL-1) administrations. In rats treated with saline, only the AA-enriched diet significantly increased anxiety-like behavior in the elevated plus maze, which was associated with increased corticosterone secretion. AA also increased the turnover of dopamine (DA), noradrenaline (NA), and serotonin (5-HT) in the amygdala and increased the prostaglandin (PG)E(2) level in the hippocampus. IL-1 administration slowed rat learning in the water maze and increased anxiety-like behavior, changes which were associated with increased homovanillic acid and 5-HT turnover, decreased NA in the hippocampus and amygdala, decreased DA in the frontal cortex, and decreased IL-10 in limbic brain regions. Increased corticosterone secretion following IL-1 administration was accompanied by increased NA turnover in the hippocampus (P < 0.05) and increased PGE(2) concentration (P < 0.01) in the limbic brain regions. Of the 3 diets tested, only EPA attenuated IL-1-induced behavioral changes (P < 0.05 or 0.01), which was associated with the modulation of EPA on the neuroendocrine and immune changes induced by IL-1. GLA reduced hippocampal PGE(2) concentration in rats given IL-1 (P < 0.01). AA did not counteract any of the changes induced by IL-1. These results suggest that EPA, GLA, and AA play different roles in the neuroendocrine-immune network.