New data presented on the effect of EPA therapy in statin-treated patients and on endothelial function in exploratory studies
Amarin Corporation plc has announced two posters presented at the annual meeting of the American College of Cardiology (ACC). This research adds to the growing body of clinical and pre-clinical data relevant to the use of EPA with statins.
The first poster, “Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) in Statin-Treated Patients With Elevated Cardiovascular Risk and Very High Triglyceride Levels: Results From the MARINE Study,” is an exploratory subgroup analysis of results from Amarin’s MARINE trial of Vascepa® (icosapent ethyl) and observed that, compared to placebo in statin-treated patients with elevated cardiovascular risk and very high triglycerides (TGs), Vascepa administered at 4 g/day significantly lowered TGs and improved other parameters relevant to cardiovascular health without raising LDL (“bad”) cholesterol. The MARINE study and this subgroup analysis were led by Harold Bays, MD, Medical Director and President, Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY.
The second poster, a pre-clinical study titled, “Eicosapentaenoic Acid and Atorvastatin Active Metabolite, Alone or in Combination, Reversed Glucose- and Oxidized LDL-Induced Endothelial Dysfunction Measured Ex Vivo in Rats,” noted that, independently and in combination, EPA and the active metabolite of atorvastatin improved endothelial function measured in rat kidney sections. This pre-clinical research was led by R. Preston Mason, Ph.D., Department of Medicine, Division of Cardiology, Brigham & Women’s Hospital, Harvard Medical School, and president and founder, Elucida Research LLC.
“The results of these two studies add to the growing body of clinical and pre-clinical data on the effects of EPA when combined with statins under the conditions studied,” said Steven Ketchum, Ph.D., president of research and development and chief scientific officer at Amarin. “Amarin’s REDUCE-IT trial, examining the effect of EPA therapy on top of statin therapy in at-risk patients with elevated triglycerides has reached target enrollment and will provide needed cardiovascular outcomes data for this important patient population.”
About the Presented Research
Dr. Bays’ analysis was based on a subgroup of the MARINE trial, a study designed to determine the effects of high-purity, prescription-grade icosapent ethyl (Vascepa) on patients with severe hypertriglyceridemia, including those who were also receiving statin therapy. The 12-week, double-blind, phase 3 MARINE trial included patients (n=229) with TGs between 500 mg/dL and 2000 mg/dL. Statin treatment was not mandated as part of the study’s inclusion criteria, but was used as a stratification factor. The subgroup analysis presented at ACC examined the effects of icosapent ethyl 4 g/day on fasting plasma lipid and lipoprotein parameters in the subgroup of patients from MARINE receiving stable statin therapy, with or without ezetimibe, which represented approximately 25% of the MARINE patient population.
This MARINE subgroup analysis focused on a comparison between statin-treated subjects administered 4 g/day icosapent ethyl (n=20) versus placebo (n=18), showing that, compared to placebo, icosapent ethyl significantly reduced TGs (-65%; P=0.0001), non-high-density lipoprotein cholesterol (-29%; P=0.0094), total cholesterol (-25%; P=0.0045), very-low-density lipoprotein cholesterol (-46%; P=0.0185), and RLP-C (-57%; P=0.0198) and numerically (all P > 0.05) reduced ApoB (-7%), oxLDL (-10%), and ApoC-III (-23%). The reductions seen in the study were not associated with a significant increase in LDL-C (-2%) or change in high-density lipoprotein cholesterol (+2%) (P > 0.05 vs placebo). As with many subgroup analyses, a limitation of this analysis is the small sample size, but the results are nonetheless suggestive of complementary beneficial changes in lipid and lipoprotein parameters from the addition of icosapent ethyl to statin therapy beyond statin therapy alone.
Dr. Mason’s exploratory study was designed to determine if a combination of EPA and the active metabolite of atorvastatin could improve endothelial cell function in rat kidney sections. Endothelial dysfunction, a condition where the inner lining of the blood vessels is unable to provide its normal function of vasodilation and vasoconstriction, is a precursor to cardiovascular disease. The reduction of the release of nitric oxide (NO), which allows blood vessels to function properly, is often accompanied by a concomitant increase in peroxynitrite (ONOO-) and is the primary cause of endothelial dysfunction. Increases in NO and the ratio of NO/ ONOO-, along with decreases in ONOO-, are considered indicators of improved endothelial function.
This research tested the separate and combined effects of EPA and the active metabolite of atorvastatin in rat kidney sections exposed to oxidized LDL (oxLDL) and high glucose levels. The combination of EPA and atorvastatin active metabolite increased NO release by 298% (P < 0.001), decreased the release of ONOO- by 32% (P < 0.05), and increased the NO/ONOO- ratio from 0.26 to 1.51 (P < 0.001). The researchers concluded that the combined effects of EPA and the active metabolite of atorvastatin on the release of nitric oxide (NO) and the NO/ONOO- ratio were significantly greater than what was observed for the active metabolite of atorvastatin alone.
Amarin’s clinical development program for Vascepa includes a trial known as REDUCE-IT, the first multinational cardiovascular outcomes study evaluating the benefit of high-dose EPA therapy as an add-on to statins in patients with high cardiovascular risk who, despite stable statin therapy, have elevated triglyceride levels. The company announced last week that it has achieved its target enrollment of 8,000 patients for the trial and that an interim analysis by the independent Data Monitoring Committee of the REDUCE-IT trial is expected within the next six months.
Additional information on MARINE, REDUCE-IT and Amarin’s other clinical studies of Vascepa can be found at www.clinicaltrials.gov.