Icosapent Research Articles

Dyslipidemia Treatment and Lipid Control in US Adults with Diabetes by Sociodemographic and Cardiovascular Risk Groups in the NIH Precision Medicine Initiative All of Us Research Program.

Real-world data on lipid levels and treatment among adults with diabetes mellitus (DM) are relatively limited. We studied lipid levels and treatment status in patients with DM across cardiovascular disease (CVD) risk groups and sociodemographic factors. In the All of Us Research Program, we categorized DM as (1) moderate risk (≤1 CVD risk factor), (2) high risk (≥2 CVD risk factors), and (3) DM with atherosclerotic CVD (ASCVD). We examined the use of statin and non-statin therapy as well as LDL-C and triglyceride levels. We studied 81,332 participants with DM, which included 22.3% non-Hispanic Black and 17.2% Hispanic. A total of 31.1% had ≤1 DM risk factor, 30.3% had ≥2 DM risk factors, and 38.6% of participants had DM with ASCVD. Only 18.2% of those with DM and ASCVD were on high-intensity statins. Overall, 5.1% were using ezetimibe and 0.6% PCSK9 inhibitors. Among those with DM and ASCVD, only 21.1% had LDL-C < 70 mg/dL. Overall, 1.9% of participants with triglycerides ≥ 150 mg/dL were on icosapent ethyl. Those with DM and ASCVD were more likely to be on high-intensity statins, ezetimibe, and icosapent ethyl. Guideline-recommended use of high-intensity statins and non-statin therapy among our higher risk DM patients is lacking, with LDL-C inadequately controlled.

The Formation of Diradylglycerol Molecular Species in Murine Peritoneal Macrophages Varies Dose-Dependently with Dietary Purified Eicosapentaenoic and Docosahexaenoic Ethyl Esters

Substantial effects of dietary fish oil-derived fatty acid ethyl esters on the metabolism of diradylglycerol (DG) have recently been described. We undertook to isolate the separate effects of (n-3) eicosapentaenoic acid (EPA) and (n-3) docosahexaenoic acid (DHA) on DG metabolism. For 3 wk, male C57BL/6 mice were fed one of six purified diets in which the lipid component was either 3 g/100 g corn oil ethyl ester (COEE) (control diet) or 1 g/100 g COEE plus 2 g/100 g of EPA ethyl ester (EPEE), DHA ethyl ester (DHEE) or an EPEE:DHEE mixture. Peritoneal macrophages were analyzed for DG content and for molecular species distributions of DG and phospholipid classes. We found that the degree of incorporation of EPA and DHA into DG in macrophages was dependent on the dietary concentration of EPEE and DHEE, under basal conditions and after stimulation with platelet-activating factor, phorbol myristate acetate and ionomycin. Incorporation of EPA and DHA into phospholipids was also significant and dose dependent in each phospholipid class. For both DG and phospholipid molecular species, the incorporation of EPA in the sn-2 position was considerably greater than that of species with DHA under conditions of equimolar dietary content. These results demonstrate that 1) incorporation of EPA and DHA into DG are independent and dependent on dietary content, 2) EPA is incorporated with greater affinity than DHA and 3) these effects on DG metabolism seem to result from corresponding effects on parent membrane phospholipids. Physiologically and therapeutically relevant differences may exist between EPA and DHA.

Icosapent ethyl for reducing the risk of cardiovascular events

Icosapent ethyl (Vazkepa) is an omega‐3 fatty acid prodrug indicated for reducing the risk of cardiovascular events in statin‐treated patients. This article summarises the clinical trial evidence for its efficacy and its place in therapy.

Icosapent ethyl alleviates acetic acid-induced ulcerative colitis via modulation of SIRT1 signaling pathway in rats.

Ulcerative colitis (UC) is a global inflammatory bowel disease. This study aimed to assess the effects of icosapent ethyl on acetic acid-induced colitis in rats as well as the underlying mechanisms involved. 36 male Wister rats were equally divided into six groups: control, UC, mesalamine 100mg/kg, icosapent 150mg/kg, icosapent 300 mg/kg, and EX527-icosapent 300mg/kg groups. Except for control group, UC was induced by acetic acid instillation into colon. Drugs were administered once daily for one week then under thiopental anaesthesia, colons were excised. Colitis macroscopic and microscopic scores were assessed. A part of colon was homogenized for detection of malondialdehyde (MDA), inerleukin1 (IL-1β), tumor necrosis factor (TNF-α), superoxide dismutase (SOD), phosphorylated Akt (pAkt) and caspase 3 levels. Silent information regulator 1 (SIRT1), heme oxygenase 1 (HO-1), and nuclear factor erythroid 2 (Nrf2) mRNA expressions were detected. Mallory-stained colonic sections were examined for collagen fibres detection. Immunohistochemistry of NF-κB and p53 expressionsin colonic sections were assessed. Acetic acid induced colitis with increments in MDA, IL-1β, TNF-α, and caspase 3 levels while decreased SOD, pAkt, SIRT1, HO-1, and Nrf2 with increased collagen fibres as well as NF-κB and p53. Icosapent decreased macro& microscopic colitis scores, MDA, IL-1β, TNF-α, and caspase 3 levels while increased SOD, pAkt, SIRT1, HO-1, and Nrf2 with decreased collagen fibres as well as NF-κB and p53. The effects of icosapent 300mg/kg were similar to mesalamine. Icosapent effects were antagonized by EX527. Icosapent alleviated acetic acid-induced colitis via its anti-inflammatory, antioxidant, and anti-apoptotic effects mediated in part by SIRT1 pathway activation.

Omega-3 Fatty Acids in Cardiovascular Disease and Diabetes: a Review of Recent Evidence.

Omega-3 fatty acids (n-3 FA) lower triglycerides, have anti-inflammatory properties, and improve metabolism. Clinical evidence of cardiovascular benefit with omega-3 fatty acids is mixed. We discuss mechanisms providing biological plausibility of benefit of omega-3 fatty acids in cardiovascular risk reduction and review clinical trials investigating the benefits of prescription omega-3 fatty acids in dyslipidemia, atherosclerotic cardiovascular disease (ASCVD), and diabetes. Although early trials showed no benefit of omega-3 fatty acids in ASCVD, the REDUCE-IT trial noted significant risk reduction in ASCVD events with highly purifiedEPA (icosapent ethyl) use which has changed the landscape for currently available therapeutic options. However, other large trials like STRENGTH and VITAL, which used different formulations of prescription omega-3 fatty acids, did not note significant cardiovascular risk reduction. Thus the effectiveness of omega-3 fatty acids for cardiovascular disease prevention is an ongoing topic of debate. A relative paucity of studies examining benefits for glycemic outcomes in persons with diabetes exists; however, fewstudies have suggested lack of benefit to date. Significant residual cardiovascular risk exists for individuals with hypertriglyceridemia. Prescription omega-3 fatty acids are more commonly used for CV risk reduction in these patients. Clinical guideline statements now recommend icosapent ethyl use for selected individuals with hypertriglyceridemia to reduce cardiovascular eventsgiven recent evidence from theREDUCE-IT trial. Nonetheless, data from other large scale trials has been mixed, and future research is needed to better understand how different preparations of omega-3 may differ in their cardiovascular and metabolic effects, and the mechanisms for their benefit.

Prevention of progressive hearing loss in a mouse model of diabetes by oral intake of eicosapentaenoic acid ethyl ester

Background The prevalence of hearing impairment in patients with diabetes was significantly higher, and the development of preventive methods is desirable. Aims/objectives This study examined the effects of eicosapentaenoic acid (EPA) administration on the prevention of early hearing loss in diabetic mice. Materials and methods Tsumura, Suzuki, Obese Diabetes (TSOD) mice were used as a model of diabetes and Tsumura, Suzuki, Non Obesity (TSNO) mice were used as controls. The animals were divided into three groups: the TSNO group and the TSOD (EPA−) group (provided sunflower oil), and the TSOD (EPA+) group (provided EPA). Auditory brainstem responses (ABRs) were measured and the cochlea was evaluated histologically. Results The TSOD (EPA+) group showed a lower tendency to increase thresholds than the TSOD (EPA−) group. The TSOD (EPA+) group had a significantly lower ABR threshold than the TSOD (EPA−) group from 11 to 14 months of age at 4 kHz. Narrowing of the capillary lumens in the stria vascularis and thickening of the vessel wall in the modiolus were observed in the TSOD (EPA−) group. Conclusions and significance It was suggested that the suppression of cochlear vascular atherosclerosis by EPA administration in TSOD mice suppressed early age-related hearing loss.

Generalizability of the REDUCE-IT trial to South Asians with cardiovascular disease

South Asians (SAs) represent ∼25% of the world's population and account for >50% of global cardiovascular (CV) deaths, yet they continue to be underrepresented in contemporary clinical trials. The REDUCE-IT study demonstrated in a high-risk and predominantly White population that icosapent ethyl (IPE) lowered major adverse cardiovascular events by 25%. We sought to determine the generalizability of these results to a high-risk population of SAs with established CV disease living in Canada. This was a cross-sectional observational study of 200 statin-treated SAs (≥45 years) with atherosclerotic CV disease (ASCVD) (NCT05271591). SA ethnicity was self-identified as being of Anglo-Indian, Bangladeshi, Bengali, Bhutanese, Goan, Gujarati, Indian, Jatt, Kashmiri, Maharashtrian, Malayali, Nepali, Pakistani, Punjabi, Sindhi, Sinhalese, Sri Lankan, Tamil, Telugu, or other SA. ASCVD was defined as the presence of coronary, carotid, or peripheral atherosclerosis. Mean age of the cohort was 67 years, where 82% were men and 57% had diabetes. The predominant ASCVD phenotype was coronary artery disease (94%). Mean (SD) baseline LDL-C and triglycerides were 1.70 (0.8) mmol/L and 1.42 (1.0) mmol/L, respectively. Three-quarters were on high-intensity statin therapy. According to the Health Canada/Canadian Cardiovascular Society Guidelines and FDA-approved indication, 33% and 25% of the participants were, respectively, eligible for IPE. A large proportion of high-intensity, statin-treated, high-risk patients with ASCVD and of self-reported SA ethnicity are eligible for IPE. These data have important translational implications for SAs who are at a disproportionately higher risk of CV morbidity and mortality. This study was funded by an unrestricted grant provided by HLS Therapeutics Inc, Canada.

Highly Valuable Fish Oil: Formation Process, Enrichment, Subsequent Utilization, and Storage of Eicosapentaenoic Acid Ethyl Esters.

In recent years, as the demand for precision nutrition is continuously increasing, scientific studies have shown that high-purity eicosapentaenoic acid ethyl ester (EPA-EE) functions more efficiently than mixed omega-3 polyunsaturated fatty acid preparations in diseases such as hyperlipidemia, heart disease, major depression, and heart disease; therefore, the market demand for EPA-EE is growing by the day. In this paper, we attempt to review EPA-EE from a whole-manufacturing-chain perspective. First, the extraction, refining, and ethanolysis processes (fish oil and ethanol undergo transesterification) of EPA-EE are described, emphasizing the potential of green substitute technologies. Then, the method of EPA enrichment is thoroughly detailed, the pros and cons of different methods are compared, and current developments in monomer production techniques are addressed. Finally, a summary of current advanced strategies for dealing with the low oxidative stability and low bioavailability of EPA-EE is presented. In conclusion, understanding the entire production process of EPA-EE will enable us to govern each step from a macro perspective and accomplish the best use of EPA-EE in a more cost-effective and environmentally friendly way.

The effect of icosapent ethyl on left atrial and left ventricular morphology.

Atrial fibrillation (AF) is a common arrhythmia associated with poor outcomes. N-3 fatty acids have been shown to provide significant cardiovascular risk reduction, but they may exacerbate the risk of AF. The pathway by which N-3 fatty acids may be arrhythmogenic is unknown. One possible mechanism involves cardiac chamber morphology alteration. The purpose of this study was to investigate the effect of icosapent ethyl (IPE) on left atrial (LA) size and left ventricular (LV) mass. This study used coronary computed tomographic angiography images gathered from the Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis (EVAPORATE) trial. EVAPORATE was a randomised, double-blind, placebo-controlled study finding a significant reduction in coronary atherosclerosis progression in patients with residually elevated triglycerides despite statin therapy on 4 g IPE daily versus 4 g placebo daily. Computed tomography images were used to measure LA size and LV mass at 0 and 18 months. Of 80 enrolled patients, 68 were included in the final analysis. Baseline demographics and risk factors were similar between IPE and placebo cohorts. LA anterior- posterior diameter measured on axial (p=0.51) and sagittal (p=0.52) orientations were not different over time. Also, there was no difference between groups in the change in LA volume (p=0.84). Change in LV mass was similar between groups (p=0.13). In conclusion, this study did not detect differences in LA size or LV mass over 18 months between patients on 4 g daily IPE versus placebo.

Icosapent ethyl use in clinical practice: current and future directions

Icosapent ethyl use in clinical practice: current and future directions

Emphasis on Icosapent Ethyl for Cardiovascular Risk Reduction: A Systematic Review.

Despite the widespread use of lipid-lowering agents such as statins, cardiovascular disease (CVD) remains the leading cause of mortality worldwide. Icosapent ethyl (IPE) (Vascepa), an ethyl ester of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA), has gained widespread popularity as an adjunctive agent that targets multiple and additional mechanisms linked to the incidence of cardiovascular (CV) events and the causative pathway of atherosclerosis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 standards were used to conduct this systematic review. In this review, we assessed various studies from PubMed, PubMed Central (PMC), and Google Scholar to evaluate the mechanisms of action and beneficial effects of IPEin the reduction ofCVDoutcomes. The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) has demonstrated a significant reduction in CV mortality with 4 g/day IPE as compared to placebo. All other trials and observational studies have supported the role of Vascepa in hypertriglyceridemia and CV risk reduction. In conclusion, the use of IPE has been shown to significantly reduce triglyceride levels and reduce CV risks in patients receiving optimal statin therapy.

RETRACTED: Cardiovascular outcomes of ethyl eicosapentaenoic acid in diabetes mellitus: A meta-analysis.

We aim to conduct a comprehensive meta-analysis encompassing all studies to assess the efficacy of Vascepa in patients with diabetes mellitus (DM) in preventing or treating existing coronary artery disease (CAD). Digital databases were queried. Odds ratios (OR) were calculated for the following outcomes: composite outcome, all-cause mortality, and cardiovascular mortality. A total of 4 randomized control trials (33,092 patients; Vascepa n=16586; Placebo n=16506) were included in our analysis. The overall mean age was 64.3 years old (Vascepa=64.3 years; Placebo=64.3 years). The sample was 61.5% male (Vascepa=60.8%; Placebo=62.1%). In patients with DM, Vascepa was found to have no significant effect on the primary composite outcome (OR 0.97, 95%CI 0.91-1.04, p>0.05), all-cause mortality (OR 0.96, 95%CI 0.90-1.03, p>0.05), and cardiovascular mortality (OR 0.90, 95%CI 0.74-1.10, p>0.05). Subgroup analysis by Vascepa type and treatment type was similarly non-significant. Our study concluded that Vascepa did not affect cardiovascular outcomes in patients with DM.

Treatment of hypertriglyceridaemia with icosapent ethyl in patients with high/very high cardiovascular risk. Consensus document of the Sociedad Española de Cardiología [Spanish Society of Cardiology] and the Sociedad Española de Diabetes [Spanish Diabetes Society

The Working Groups of Cardiovascular Pharmacotherapy of the Sociedad Española de Cardiología and Cardiovascular Disease of the Sociedad Española de Diabetes have prepared a consensus document on the treatment of hypertriglyceridaemia in patients with high/very-high-cardiovascular risk with icosapent ethyl, a highly purified and stable eicosapentaenoic acid ethyl ester. This document is necessary since there are differences among the three main omega-3 fatty acids and there is large-scale clinical evidence with icosapent ethyl that demonstrates that in addition to its efficacy in lowering triglyceridaemia, it reduces the risk of cardiovascular events in both patients with atherosclerotic cardiovascular disease and in those with type 2 diabetes, with a good safety profile. The number needed to treat to avoid a major cardiovascular event is analysed, comparing it with other pivotal studies of pharmacological intervention in cardiovascular prevention, and an estimate of the Spanish population likely to be treated with ethyl icosapent is carried out. These recommendations are of interest to all clinicians who manage patients with lipid metabolism disorders, cardiovascular disease and diabetes.

Abstract 15024: High Concentration Mineral Oil, Corn Oil and Their Constitutive Fatty Acids Do Not Influence Low-Density Lipoprotein (LDL) Oxidation Rates in vitro

Introduction: LDL transports dietary long chain fatty acids, constituents that may influence rates of lipid oxidation. Modified LDL promotes foam cell formation during atherosclerosis. The omega-3 fatty acid (n3-FA) eicosapentaenoic acid (EPA) administered as icosapent ethyl (IPE), reduced cardiovascular events in REDUCE-IT compared to mixed n3-FAs in similar high-risk patients (STRENGTH). Some have attributed these discordant outcomes, in part, to placebo choice (mineral versus corn oil) despite very limited oral absorption. We compared the effects of these oils and various FAs on rates of LDL oxidation at supra-pharmacologic doses. Methods: LDL was isolated from human plasma by isopycnic centrifugation, separated into test samples of 100 μg/mL before being incubated at 37°C for 30 min with pharmaceutical grade mineral or corn oil at high concentrations (100 μg/mL) that are comparable to treatment achieved n3-FAs (4 g/d) that have high oral absorption. We also tested FAs contained in these oils, including stearic acid (18:0), arachidic acid (20:0), and linoleic acid (18:2, n-6) as well as ascorbic acid (10 μM) and a water-soluble analog of vitamin E (Trolox, 10 μM) as controls. All samples then underwent copper-induced oxidation (20 μM) monitored by formation of malondialdehyde (MDA). Results: MDA formation increased from 0.28 ± 0.03 to 9.96 ± 0.58 μM ( p &lt;0.001) with vehicle treatment from 0-2 h. Addition of either mineral or corn oil at 100 μg/mL did not significantly influence rates of MDA formation at 2 h (0.02% and 1.93% change vs vehicle, respectively). Nor did we observe any antioxidant activity with constituent FAs stearic acid, arachidic acid, or linoleic acid, FAs with no or two double bonds. As antioxidant controls, ascorbic acid and Trolox both reduced LDL oxidation by 93% and 94% (0.71 ± 0.11 and 0.62 ± 0.04 to 9.96 ± 0.58 μM, p &lt;0.001) after 2 h. Conclusions: Neither mineral nor corn oils affected LDL oxidation even at supra-pharmacologic concentrations. Beyond poor oral absorption, mineral oil and its constituent fatty acids did not affect LDL oxidation, a property related to mechanisms of atherosclerosis.

Abstract 13683: Eicosapentaenoic Acid (EPA) Decreases Endothelin Converting Enzyme-1 Expression and Improves Nitric Oxide Release in Pulmonary Endothelium Following Challenge With Air Pollutants

Background: Air pollution particulate matter (PM) contributes to global mortality and chronic conditions, especially cardiovascular (CV) disease. Exposure to PM and cytokines like IL-6 cause endothelial cell (EC) dysfunction, leading to nitric oxide synthase (eNOS) uncoupling. The omega-3 fatty acid EPA improves eNOS coupling and reduces vascular inflammation. REDUCE-IT showed that treatment with icosapent ethyl (IPE), a purified EPA ethyl ester, reduced composite CV events. We compared the effects of EPA on pulmonary EC (PEC) function and protein expression following challenge with PMs versus IL-6. Methods: PECs were treated with EPA (40 μM) or equivolume vehicle for 2 h and then challenged with IL-6 (12 ng/mL) or PM (50 μg/mL) collected from urban environments (“urban PM”) for up to 8 h. Proteomic analysis was performed using LC/MS to measure relative protein expression. Significant ( p &lt;0.05) changes between treatment groups (&gt;1-fold) were analyzed by bioinformatic packages. Biological pathways were analyzed by gene set enrichment analysis (GSEA). In parallel, cells were stimulated with calcium ionophore to elicit nitric oxide (NO) and peroxynitrite (ONOO – ) release as assayed by tandem porphyrinic nanosensors; the NO/ONOO – ratio indicates eNOS coupling efficiency. Results: Challenge with IL-6 and urban PM caused eNOS uncoupling as evidenced by a decreased NO/ONOO – ratio of 35% (1.43 ± 0.04 vs. 2.19 ± 0.02, p &lt;0.001) and 50% (1.22 ± 0.07 vs. 2.42 ± 0.15 , p &lt;0.001), respectively, compared to control. EPA increased the NO/ONOO – ratio relative to both IL-6 (39%; 1.99 ± 0.11, p &lt;0.001) and urban PM (39%; 1.69 ± 0.14 , p &lt;0.05). Proteomics revealed that EPA decreased expression of endothelin converting enzyme-1 (ECE1) relative to both IL-6 (1.2-fold, p = 0.017) and urban PM (1.1-fold, p = 0.045). GSEA showed significant modulations to 18 and 35 proteins within the neutrophil degranulation pathway (GO:0043312) with EPA treatment relative to IL-6 and urban PM ( p &lt;0.0001 in both comparisons). Conclusion: EPA favorably reversed EC dysfunction and expression of inflammatory proteins and pathways following challenge with air pollution PMs similar to IL-6. These broad anti-inflammatory actions may contribute to reduced CV risk with EPA as observed in outcome trials.

Abstract 13685: Eicosapentaenoic Acid (EPA) Inhibits Low-Density Lipoprotein (LDL) Oxidation Compared to Docosahexaenoic Acid (DHA) and Mineral Oil in vitro

Introduction: Oxidized LDL triggers inflammation during the initiation and progression of atherosclerotic plaque. The omega-3 fatty acid (n3-FA) EPA administered as icosapent ethyl (IPE), reduced cardiovascular (CV) events in REDUCE-IT due, in part, to potential antioxidant and anti-thrombotic activity. By contrast, mixed n3-FA containing docosahexaenoic acid (DHA) have failed to reduce CV events in similar high-risk patients (STRENGTH). Some have raised concerns over the relationship between these discordant outcomes and placebo choice (mineral oil) as well as DHA content. We compared the effects of these compounds on oxidation of LDL where such ingested fatty acids are concentrated and transported. Methods: LDL was isolated from human plasma by isopycnic centrifugation, separated into test samples of 100 μg/mL, and incubated at 37°C for 30 min with pharmaceutical grade mineral oil, EPA, DHA or vehicle at equimolar levels (10 μM). All samples were then subjected to copper sulfate-induced oxidation (20 μM) monitored by formation of malondialdehyde (MDA). Ascorbic acid at equimolar levels served as a control. Results: LDL oxidation increased 30-fold (0.28±0.03 vs 8.72±0.54 μM; p &lt;0.001) after 4 h and the rate was unaffected by addition of mineral oil. By contrast, EPA significantly inhibited LDL oxidation; after 4 h, EPA inhibited MDA levels by 75% compared with vehicle (8.72±0.54 vs 2.20±0.36 μM; p &lt;0.001). While DHA exhibited antioxidant activity at 2 hours at a level less than EPA (1.15±0.54 vs 3.00±1.08 μM; p &lt;0.05), it exhibited no antioxidant activity after 4 h. Like DHA, ascorbic acid also reduced LDL oxidation only up to 2 h. Conclusions: These data support sustained LDL antioxidant effects for EPA compared with DHA, ascorbic acid, or mineral oil. The longer-term antioxidant actions of EPA may contribute to reduced events in outcome trials compared to mixed n3-FA formulations, independent of placebo selection.

PSUN270 Magnified Risk of Pancreatitis by GLP-1: A Case of Necrotizing Pancreatitis in a Patient on Dulaglutide with Baseline Elevated Triglycerides

Abstract Introduction Glucagon-like peptide 1 receptor agonists (GLP-1 RA), used in the treatment of diabetes mellitus, have been associated with pancreatitis in both animal studies and clinical trials. Furthermore, GLP-1 RA are associated with increased levels of serum lipase and amylase, possibly indicating resultant pancreatic inflammation.1 While there is debate on the actual degree of risk of pancreatitis in patients on GLP-1 RA, there may be individuals who are at higher risk due to baseline comorbidities that may have their risk of pancreatitis further potentiated by treatment with GLP-1 RA. We present a case in which a patient with baseline moderately elevated triglycerides on long term GLP-1 RA develops necrotizing pancreatitis after minimal alcohol intake. Case A 46-year-old man with type 2 diabetes mellitus, hyperlipidemia, and depression presented with one day history of severe right upper quadrant abdominal pain, nausea, and non-bloody, non-bilious vomiting. He also endorsed subjective fevers and chills, shortness of breath, chest pain, and constipation. He reported that he had drank one bottle of sparkling wine the day prior but denied drinking regularly. Labs and imaging were consistent with acute necrotizing pancreatitis with elevated lipase (502 U/L), elevated triglycerides (TG) (3,480 mg/dL), and CT abdomen/pelvis showing focal hypoattenuation/edema of the pancreatic head with surrounding fat stranding. Subsequent MRI abdomen showed evolving necrotic pancreatitis with focal area of nonenhancement in the pancreatic head. He denied any history of gallstones, recent trauma, diarrhea, weight loss, or prior pancreatitis. Review of his medications was notable for dulaglutide for management of his diabetes. He also had a history of consistently elevated TG to the mid-300s mg/dL as far back as 3 years ago. Patient was ultimately managed conservatively with intravenous fluids with resolution of symptoms and downtrend of lipase and triglycerides. He was discharged on fenofibrate and icosapent ethyl for further triglyceride control. Discussion While several META analyses have not shown significant association between GLP-1 RA and pancreatitis, there still is a proportion of patients who have developed pancreatitis on GLP-1 RA.2 Our patient had baseline elevated triglycerides, but they were below the typical threshold for treatment. With minimal alcohol consumption, he still developed pancreatitis. We suspect that his risk for pancreatitis was magnified by his GLP-1 RA. We believe that in patients such as ours who have baseline independent risk factors for pancreatitis, GLP-1 RA should be carefully considered before initiation. 1. Trujillo J. Safety and tolerability of once-weekly GLP-1 receptor agonists in type 2 diabetes. J Clin Pharm Ther. 2020;45 Suppl 1(Suppl 1): 43-60. doi: 10.1111/jcpt.13225 2. Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials. Diabetes Res Clin Pract. 2014;103(2): 269-275. doi: 10.1016/j.diabres.2014.01.010 Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Icosapent Ethyl Supplementation and Cardiovascular Prevention—Implications of Evolving Data

This Viewpoint discusses the findings of the Reduction of Cardiovascular Events With Icosapent Ethyl Intervention Trial regarding the use of icosapent ethyl in moderate- to high-risk patients with fasting triglyceride levels greater than 135 mg/dL.

Ethyl EPA and ethyl DHA cause similar and differential changes in plasma lipid concentrations and lipid metabolism in subjects with low-grade chronic inflammation

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to similarly lower plasma TG concentrations but differentially regulate plasma LDL-C and HDL-C concentrations. The aim of this study was to evaluate the common and differential effects of these ω-3 fatty acids on plasma lipids and lipoproteins and to assess the metabolic mechanisms of the effects. In a randomized, double-blind, crossover study, we assessed the effect of 10-week supplementation with 3 g/d pure EPA and pure DHA (both as ethyl ester, ≥97% purity) on plasma lipid and lipoprotein concentrations and activities of lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) in 21 older (>50 y) men and postmenopausal women with some characteristics of metabolic syndrome and low-grade chronic inflammation. Both EPA and DHA lowered plasma TG concentrations and increased LDL-C/apoB and HDL-C/apoA-I ratios, but only DHA increased LDL-C concentrations. The reductions in plasma TG were inversely associated with the changes in LPL activity after both EPA and DHA supplementation. EPA lowered CETP, while DHA lowered LCAT activity. EPA and DHA worked differently in men and women, with DHA increasing LPL activity and LDL-C concentrations in women, but not in men. EPA and DHA exerted similar effects on plasma TG, but differences were observed in LDL-C concentrations and activities of some enzymes involved in lipoprotein metabolism. It was also noted that EPA and DHA worked differently in men and women, supporting sex-specific variations in lipoprotein metabolism.

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 (0.5-4g) 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 (0.5-4g) immediately after breakfast or EPA-E (0.9g) immediately after breakfast and dinner for 11days 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 1g once daily, and the mean Css,min and the mean AUCss,0-24h of MND-2119 administered as 2g once daily were higher than those of EPA-E administered as 0.9g 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.