Study Shows Unique Protection of Small Dense LDL From Oxidative Damage That Results in Endothelial Cell Benefits
BEDMINSTER, NJ and DUBLIN, IRELAND--( March 16, 2015) - Amarin Corporation Plc (AMRN) announced today the presentation of findings from a new in vitro study showing that pretreatment with eicosapentaenoic acid (EPA), an omega-3 fatty acid, reduced oxidation of small dense LDL (sdLDL) and resulted in improved endothelial function when compared to other triglyceride (TG)-lowering agents, including fenofibrates, niacin and gemfibrozil. The research was presented today at a peer-reviewed poster session at the American College of Cardiology Scientific Session in San Diego, California.
Endothelial cell dysfunction contributes to increased risk for atherosclerosis and heart disease and is characterized by reduced nitric oxide (NO) presence and increased production of the cytotoxic peroxynitrite anion, which can lead to an inflammatory response in blood vessels.(i),(ii) Endothelial cell dysfunction has been observed in patients with various cardiovascular risk factors, such as dyslipidemia and diabetes.(iii),(iv),(v) In addition, evidence suggests that sdLDL is highly atherogenic and associated with plaque formation in human arteries as compared to larger LDL particles;(vi),(vii) and oxidation of sdLDL further increases its atherogenicity.(viii)
"As has been shown in a number of recent studies, oxidized LDL -- in particular oxidized sdLDL -- contributes to endothelial dysfunction in the development of atherosclerosis and may need to be addressed in treating at-risk patients, such as those with high triglycerides," said R. Preston Mason, Ph.D., Department of Medicine, Division of Cardiology, at the Harvard Medical School-Brigham and Women's Hospital in Boston and lead author of the study. "Treatments that can reduce sdLDL oxidation and slow or even reverse endothelial cell dysfunction should be studied further for potential benefit. The findings of this study show that the omega-3 fatty acid EPA may reduce oxidative stress and improve endothelial function, and may thereby provide potential benefits beyond lipid-lowering that are not observed with other triglyceride lowering agents."
Researchers found that EPA pretreatment protected sdLDL particles from oxidative damage, reducing sdLDL oxidation by >90% (p<0.001) as compared with the absence of EPA treatment. When applied directly to human umbilical vein endothelial cells (HUVECs), the vehicle-treated oxidized sdLDL significantly reduced NO release by 20% as compared with non-oxidized sdLDL. Following exposure to sdLDL that had been treated with EPA prior to oxidation, however, HUVEC release of NO increased significantly by 53% and 23%, as compared with treatment with oxidized sdLDL and non-oxidized sdLDL treatments, respectively. All of the other TG-lowering agents failed to inhibit sdLDL oxidation, and instead resulted in significant reductions in NO release compared to vehicle-treated oxidized sdLDL.
These data add to the previously published studies indicating a unique and potent antioxidant effect for EPA on LDL particles and suggest that EPA treatment may also protect lipoproteins such as sdLDL from proatherogenic modification by oxidation and may also reduce oxidative stress in endothelial cells, potentially leading to beneficial effects on endothelial function.(ix) More study is needed and is being conducted to further explore these unique potential protective effects of EPA.
The study was supported by Amarin and led by a researcher at Brigham and Women's Hospital in collaboration with investigators at Elucida Research in Beverly, Massachusetts and Ohio University in Athens, Ohio.
Amarin Corporation plc is a biopharmaceutical company focused on the commercialization and development of therapeutics to improve cardiovascular health. Amarin's product development program leverages its extensive experience in lipid science and the potential therapeutic benefits of polyunsaturated fatty acids. Amarin's clinical program includes commitment to an ongoing outcomes study. For more information about Amarin visit www.amarincorp.com.
This press release contains forward-looking statements, including statements about the potential efficacy, safety and therapeutic benefits of EPA, including statements about the potential clinical importance of the findings presented and the potential atheroprotective benefit of EPA. These forward-looking statements are not promises or guarantees and involve substantial risks and uncertainties. Among the factors that could cause actual results to differ materially from those described or projected herein include uncertainties associated generally with in vitro research, research and development and clinical trials, including the risk that in vitro study results may not be predictive of future results in replicated in study in man and that studied parameters may not have clinically meaningful effect. A list and description of these risks, uncertainties and other risks associated with an investment in Amarin can be found in Amarin's filings with the U.S. Securities and Exchange Commission, including its most recent annual report on Form 10-K. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. Amarin undertakes no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise.
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(v) Mason RP, Kubant R, Jacob RF, et al. Am J Hypertens. 2009; 22:1160-1166.
(vi) Rizzo M, Berneis K. QJ Med. 2006; 99:1-14.
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(viii) Toth PP. Curr Vasc Pharmacol. 2014; 12:653-7.
(ix) Mason RP, Jacob RF. Biochim Biophys Acta. 2015; 1848:502-509
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