Benefits of Icosapent Ethyl Across the Range of Kidney Function in Patients With Established Cardiovascular Disease or Diabetes: REDUCE-IT RENAL.

BACKGROUND: Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease (CVD) or diabetes. Commonly used medications to treat CVD are less effective among patients with reduced kidney function. METHODS: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was a multicenter, double-blind, placebo-controlled trial that randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL) who had CVD or diabetes and 1 additional risk factor to treatment with icosapent ethyl (4 g daily) or placebo. Patients from REDUCE-IT were categorized by prespecified estimated glomerular filtration rate (eGFR) categories to analyze the effect of icosapent ethyl on the primary end point (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) and key secondary end point (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Among the 8179 REDUCE-IT patients, median baseline eGFR was 75 mL·min-1·1.73 m-2 (range, 17-123 mL·min-1·1.73 m-2). There were no meaningful changes in median eGFR for icosapent ethyl versus placebo across study visits. Treatment with icosapent ethyl led to consistent reduction in both the primary and key secondary composite end points across baseline eGFR categories. Patients with eGFR <60 mL·min-1·1.73 m-2 treated with icosapent ethyl had the largest absolute and similar relative risk reduction for the primary composite end point (icosapent ethyl versus placebo, 21.8% versus 28.9%; hazard ratio [HR], 0.71 [95% CI, 0.59-0.85]; P=0.0002) and key secondary composite end point (16.8% versus 22.5%; HR 0.71 [95% CI, 0.57-0.88]; P=0.001). The numeric reduction in cardiovascular death was greatest in the eGFR <60 mL·min-1·1.73 m-2 group (icosapent ethyl: 7.6%; placebo: 10.6%; HR, 0.70 [95% CI, 0.51-0.95]; P=0.02). Although patients with eGFR <60 mL·min-1·1.73 m-2 treated with icosapent ethyl had the highest numeric rates of atrial fibrillation/flutter (icosapent ethyl: 4.2%; placebo 3.0%; HR 1.42 [95% CI, 0.86-2.32]; P=0.17) and serious bleeding (icosapent ethyl: 5.4%; placebo 3.6%; HR, 1.40 [95% CI, 0.90-2.18]; P=0.13), HRs for atrial fibrillation/flutter and serious bleeding were similar across eGFR categories (P-interaction for atrial fibrillation/flutter=0.92; P-interaction for serious bleeding=0.76). CONCLUSIONS: In REDUCE-IT, icosapent ethyl reduced fatal and nonfatal ischemic events across the broad range of baseline eGFR categories. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

REDUCE-IT USA: Results From the 3146 Patients Randomized in the United States.

BACKGROUND: Some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. This prespecified REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial) subgroup analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States. METHODS: REDUCE-IT randomized 8179 statin-treated patients with qualifying triglycerides ≥135 and <500 mg/dL and low-density lipoprotein cholesterol >40 and ≤100 mg/dL and a history of atherosclerosis or diabetes mellitus to icosapent ethyl 4 g/d or placebo. The primary composite end point was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary composite end point was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. A hierarchy was prespecified for examination of individual and composite end points. RESULTS: A total of 3146 US patients (38.5% of the trial) were randomized and followed for a median of 4.9 years; 32.3% were women and 9.7% were Hispanic. The primary composite end point occurred in 24.7% of placebo-treated patients versus 18.2% of icosapent ethyl-treated patients (hazard ratio [HR], 0.69 [95% CI, 0.59-0.80]; P=0.000001); the key secondary composite end point occurred in 16.6% versus 12.1% (HR, 0.69 [95% CI, 0.57-0.83]; P=0.00008). All prespecified hierarchical end points were meaningfully and significantly reduced, including cardiovascular death (6.7% to 4.7%; HR, 0.66 [95% CI, 0.49-0.90]; P=0.007), myocardial infarction (8.8% to 6.7%; HR, 0.72 [95% CI, 0.56-0.93]; P=0.01), stroke (4.1% to 2.6%; HR, 0.63 [95% CI, 0.43-0.93]; P=0.02), and all-cause mortality (9.8% to 7.2%; HR, 0.70 [95% CI, 0.55-0.90]; P=0.004); for all-cause mortality in the US versus non-US patients, Pinteraction=0.02. Safety and tolerability findings were consistent with the full study cohort. CONCLUSIONS: Whereas the non-US subgroup showed significant reductions in the primary and key secondary end points, the US subgroup demonstrated particularly robust risk reductions across a variety of individual and composite end points, including all-cause mortality. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01492361.

A self-emulsifying Omega-3 ethyl ester formulation (AquaCelle) significantly improves eicosapentaenoic and docosahexaenoic acid bioavailability in healthy adults.

PURPOSE: Application of intelligent formulation design has the ability to address the poor bioavailability and improve the fasted state bioavailability of fish oils. In this study we assessed the ability of a self-emulsifying drug delivery system (SEDDS), AquaCelle®, as an additive to enhance the oral absorption of Omega-3 ethyl esters (EE) in healthy subjects under low-fat diet conditions. METHODS: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) EE were formulated with AquaCelle®. A single dose (680 mg dose of oil containing 272 mg of EPA EE and 204 mg of DHA EE), randomized, double-blind, study measured uptake of EPA and DHA over 24 h in healthy adults. Participants were randomized into two groups, receiving either the SEDDS AquaCelle® fish oil formulation or the unformulated fish oil EE as control. RESULTS: The AquaCelle® fish oil EE formulation demonstrated instant and complete emulsification on addition to water to produce an emulsion with an average diameter of 43 µm, compared to the oil alone which did not emulsify. The study revealed a significant difference in absorption (Cmax and AUC0-24h) between the AquaCelle® group and the control group. The AquaCelle® group was capable of increasing maximum plasma concentrations and absorption (AUC0-24h) of total Omega-3 (EPA + DHA) 3.7- and 7.1-fold, respectively, compared to the control. CONCLUSION: Formulating Omega-3 EE with a SEDSS concentrate (AquaCelle®) demonstrated a significant improvement in the oral absorption of Omega-3 fatty acids without requiring a high-fat meal.

Mechanistic aspects of ameliorative effects of Eicosapentanoic acid ethyl ester on methotrexate-evoked testiculopathy in rats.

Disrupted spermatogenesis and testicular injury are among the devastating outcomes of methotrexate. A major contributor to methotrexate-induced testiculopathy is oxidative damage which triggers apoptosis and altered autophagy responses. Eicosapentaenoic acid ethyl ester (EPA-E) is an antihyperlipidemic derivative of omega-3 fatty acids that exhibited affinity to peroxisome proliferator-activated receptor-γ (PPAR-γ) that possesses both antioxidant and autophagy modulating properties. This is an exploratory study aiming at assessing the effectiveness of EPA-E to alleviate testicular damage induced by methotrexate. The specific exploratory hypothesis of this experiment is: EPA-E administration for 1 week to methotrexate-treated rats reduces testicular damage compared to control rats. As a secondary outcome, we were interested in identifying the implicated mechanism that mediates the action of EPA-E. In adult male Wistar rats, testiculopathy was achieved by a single methotrexate injection (20 mg/kg, ip). Rats received vehicle, EPA-E (0.3 g/kg/day, po) alone or with selective PPAR-γ antagonist (bisphenol A diglycidyl ether, BADGE) at 30 mg/kg/day, ip for 1 week. EPA-E recuperated methotrexate-attenuated serum total testosterone while reduced testicular inflammation and oxidative stress, restoring superoxide dismutase (SOD) while reducing malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Methotrexate-induced testicular apoptosis (caspase-3 and p53) was suppressed upon EPA-E treatment. Besides, EPA-E curbed methotrexate-induced abnormal autophagy by downregulating LC3A/B and beclin-1. Interestingly, BADGE-coadministration reversed EPA-E beneficial actions. Collectively, our findings suggest PPAR-γ role in EPA-E-mediated mitigation of methotrexate-evoked testiculopathy via suppression of oxidative stress, apoptosis, as well as abnormal autophagy. Furthermore, EPA-E could be used as a preventive therapy for some testiculopathies mediated by oxidative stress.

Pharmacokinetics of Single and Multiple Oral Administration of a Self-emulsifying Formulation of Highly Purified Eicosapentaenoic Acid Ethyl Ester (MND-2119) Compared With the Nonself-emulsifying Formulation in Healthy Male Subjects.

MND-2119 is a self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester (EPA-E) designed to be administered once daily due to improved absorption compared with the nonself-emulsifying formulation. In these studies, MND-2119 was administered to healthy adult males in single or multiple doses. In the single administration study, MND-2119 (0.5-4 g) was administered under fed and fasted conditions to evaluate MND-2119 pharmacokinetics and safety under these conditions. This study showed that Cmax and AUC0-72h of plasma EPA concentration after single administration were higher under fed conditions than under fasted conditions, for all doses. In the multiple administration study, subjects received either MND-2119 (0.5-4 g) immediately after breakfast or EPA-E (0.9 g) immediately after breakfast and dinner for 11 days to compare pharmacokinetics and safety of MND-2119 to EPA-E. In this study, the rate of rise in Cmin of the plasma EPA concentration with MND-2119 decreased from days 6 to 8 after administration and was thought to have reached a steady state on day 11. The mean Css,max of MND-2119 administered as 1 g once daily, and the mean Css,min and the mean AUCss,0-24h of MND-2119 administered as 2 g once daily were higher than those of EPA-E administered as 0.9 g twice daily. No safety-related issues occurred in either study. These results suggest that MND-2119 administered once daily may achieve equivalent or higher plasma EPA concentrations compared to the nonself-emulsifying formulation administered twice daily.

JCL roundtable: Omega-3 fatty acids and cardiovascular outcomes.

The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) in 2018 demonstrated the value of an omega-3 fatty acid formulation, icosapent ethyl (eicosapentaenoic acid ethyl ester) for preventive treatment of atherosclerotic cardiovascular disease (ASCVD). This JCL Roundtable discussion brings together three experts to explore the origins and implications of REDUCE-IT and more broadly omega-3 fatty acids for mitigation of ASCVD risk. REDUCE-IT achieved a highly significant 25% reduction of major adverse cardiovascular events. It is the first trial of a triglyceride-lowering drug to gain unequivocal success in high-risk patients treated intensively with statins. It corroborates positive results from an earlier major trial using eicosapentaenoic acid (EPA) ethyl ester, the Japan EPA Lipid Intervention Study (JELIS), which included hypercholesterolemic subjects treated with low-dose statin mostly in primary prevention. Together these studies mark a new avenue for preventive treatment of ASCVD. Omega-3 fatty acids also show some promise, though less decisively, for reducing inflammation and cardiovascular mortality in a broader context.

A biphasic system based on guanidinium ionic liquid: Preparative separation of eicosapentaenoic acid ethyl ester and docosahexaenoic acid ethyl ester by countercurrent chromatography.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are high nutritional components. Evidence for unique effects of them is increasing. Further understanding of their independent biological functions urgently needs more efficient separation techniques. Nowadays, most of the commercially available fish oil products are the mixture of eicosapentaenoic acid ethyl ester (EPAEE) and docosahexaenoic acid ethyl ester (DHAEE). It will be convenient to directly separate esterified EPA and DHA without saponification pretreatment. However, it is of great challenge to separate EPAEE and DHAEE because of their extremely fat-soluble nature and the equivalent chain length rule. In this research, the suitability of green guanidinium ionic liquid (IL) in countercurrent chromatography (CCC) solvent system for the separation of them was evaluated for the first time. Compared with imidazolium IL and phosphonium IL, guanidinium IL based non-aqueous biphasic system showed more outstanding separation performance. The separation mechanism was elucidated in depth through quantum mechanical calculations. It was found that guanidinium IL acted a crucial role in the CCC separation, which resulted in difference of partition behavior of EPAEE and DHAEE via different hydrogen-bonding affinity. EPAEE and DHAEE were successfully separated by solvent system (n-heptane/methanol/propylguanidinium chloride ([C3Gun]Cl, 1:1:5%, v/v/m)) with high purity (>95%) in one step, which was not achieved beforehand. Moreover, an easy recycling procedure of IL had also been devised, which significantly reduced waste generated. It opens up a new way for reasonable design water-free two-phase solvent system for efficient separation of very non-polar lipid compounds.

[Separation of eicosapentaenoic acid ethyl ester and docosahexaenoic acid ethyl ester by simulated moving bed chromatography].

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are important ω -3 polyunsaturated fatty acids. Their physiological effects on humans are not exactly the same; therefore, the production of products with high-purity EPA or DHA monomers is significant. In this work, EPA ethyl ester (EPA-EE) and DHA ethyl ester (DHA-EE) were first separated using HPLC with poly(styrene-co-divinylbenzene) (PS/DVB) as the stationary phase. The effects of the mobile phase, PS/DVB particle diameter, and column temperature were systematically evaluated. The results showed that methanol is a suitable mobile phase, having a resolution of 2.75. By comparing resolutions, a PS/DVB particle diameter of 10 µ m was chosen; however, when the pressure drop of PS/DVB is considered, PS/DVB with a particle diameter of 20 µ m is more favorable for large-scale preparations. A column temperature of 40℃ was found to be the most feasible for maintaining efficient separation. Second, eight semi-preparative columns (150 mm×10 mm) of PS/DVB polymer were prepared for the simulated moving bed (SMB) chromatography; the homogeneity of these columns was perfect, with a relative total column porosity error of less than 1%. Finally, an EPA-EE and DHA-EE mixture was separated using the SMB chromatography, and the contents of the extract and the raffinate were determined using GC-FID. The effects of the flow rate of Zone Ⅱ and Zone Ⅲ, the flow rate of the feed, and the feed concentration were investigated. Under optimal conditions, EPA-EE and DHA-EE with favorable purities of 91.6% and 93.6%, respectively, were achievable. The recovery of the EPA-EE was 97.0% and the recovery of the DHA-EE was 91.6%. The productivity and solvent requirements were 5.97 g/(L\5h) and 1.52 L/g, respectively. Therefore, SMB chromatography is an attractive technology for the production of high-value products.

Potential benefits of eicosapentaenoic acid on atherosclerotic plaques.

Residual cardiovascular (CV) risk remains in some patients despite optimized statin therapy and may necessitate add-on therapy to reduce this risk. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, lowers plasma triglyceride levels without raising low-density lipoprotein cholesterol levels and has potential beneficial effects on atherosclerotic plaques. Animal studies have shown that EPA reduces levels of pro-inflammatory cytokines and chemokines. In clinical trials utilizing a wide spectrum of plaque imaging modalities, EPA has shown beneficial effects on plaque characteristics. Studies of patients with coronary artery disease receiving statin therapy suggest that EPA may decrease plaque vulnerability and prevent plaque progression. EPA also decreased pentraxin-3 and macrophage accumulation. A large, randomized, Japanese study reported that EPA plus a statin resulted in a 19% relative reduction in major coronary events at 5years versus a statin alone in patients with hypercholesterolemia (P=0.011). Icosapent ethyl, a high-purity prescription form of EPA ethyl ester, has been shown to reduce triglyceride levels and markers of atherosclerotic inflammation. Results of an ongoing CV outcomes study will further define the potential clinical benefits of icosapent ethyl in reducing CV risk in high-risk patients receiving statin therapy.

Effects of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) on Pharmacokinetic Parameters of Rosiglitazone in Healthy Subjects.

BACKGROUND: Icosapent ethyl is a high-purity form of eicosapentaenoic acid ethyl ester approved to reduce triglyceride levels in adults with triglycerides ≥500 mg/dL. Candidates for triglyceride-lowering therapy include patients with diabetes mellitus who may be receiving rosiglitazone. We assessed the effects of icosapent ethyl on the pharmacokinetic parameters of rosiglitazone. METHODS: Subjects received a single 8-mg oral dose of rosiglitazone alone and with oral icosapent ethyl 4 g/day in this open-label drug-drug interaction study. Pharmacokinetic end points included area under the concentration versus time curve from time zero to infinity (AUC0-inf) and maximum observed concentration (Cmax) for rosiglitazone with and without icosapent ethyl. RESULTS: Of 30 subjects enrolled, 28 completed the study. Icosapent ethyl 4 g/day at steady-state did not significantly change the single-dose AUC0-inf or Cmax of rosiglitazone 8 mg. Least squares geometric mean ratios (90% confidence interval) for AUC0-inf and Cmax of rosiglitazone given with icosapent ethyl versus rosiglitazone alone were 0.90 (87.00-93.40) and 1.01 (92.02-109.9), respectively. No serious adverse events were reported and no subject discontinued due to an adverse event. CONCLUSIONS: At steady-state concentrations, icosapent ethyl did not inhibit the pharmacokinetics of rosiglitazone. Co-administration of icosapent ethyl and rosiglitazone was safe and well tolerated.

Pharmacokinetics of Eicosapentaenoic Acid in Plasma and Red Blood Cells After Multiple Oral Dosing With Icosapent Ethyl in Healthy Subjects.

OBJECTIVE: Icosapent ethyl (IPE) is a prescription form of eicosapentaenoic acid (EPA) ethyl ester. This randomized, open-label study characterized EPA pharmacokinetics. METHODS: Four healthy subject groups received IPE for 28 days: three received 2 g/day (1 × 1,000 mg BID, 2 × 1,000 mg QD, or 2 × 500 mg BID); one received 4 g/day (2 × 1,000 mg BID) administered with meals. Blood sampling was before the morning dose on days 1, 14, 26, 28, and at specified intervals during an 18-day pharmacokinetic period. EPA was measured in plasma (total and unesterified) and red blood cells (RBCs) by liquid chromatography/tandem mass spectrometry. RESULTS: Mean plasma total EPA increased from 19 µg/mL to a peak (Cmax) of 366 µg/mL at 5 hours postdosing 4 g/day IPE on Day 28. Mean RBC EPA Cmax after 4 g/day was 89 µg/mL (baseline, 12 µg/mL). Mean steady state (SD) for half-life, clearance, and volume of distribution of total EPA were 79 (47) hours, 757 (283) mL/h, and 82 (56) L, respectively. Steady state for total and unesterified plasma EPA was reached by Day 28, whereas RBC levels were still increasing. CONCLUSIONS: EPA pharmacokinetic profile demonstrated a slowly cleared, extensively distributed molecule with dose linearity and comparable exposures with BID and QD regimens.