Icosapent Research Articles

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 <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 <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 <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.

Icosapent Ethyl diminishes CVD risk in smokers: REDUCE-IT smoking

Abstract Background/Introduction Cigarette smoking is associated with increased risk of cardiovascular (CV) events with effective treatment currently limited to smoking cessation. REDUCE-IT, a multinational, double-blind trial, randomised 8179 statin-treated patients with controlled low density lipoprotein cholesterol, elevated triglycerides, and CV risk, to icosapent ethyl (IPE) 4 grams/day or placebo, with a median of 4.9 years of follow-up. IPE reduced the primary composite (CV death, nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularisation, or hospitalisation for unstable angina) and key secondary composite (CV death, nonfatal MI, or nonfatal stroke) endpoints 25% and 26%, respectively (each P<0.0001), and individual components including stroke (28%), MI (31%), cardiac arrest (48%), and sudden cardiac death (31%) (all P≤0.01). Purpose To evaluate the effects of IPE on the risk of CV events and safety measures in patients by history of smoking. Methods The effect of IPE on first and total primary and key secondary endpoints was evaluated in the REDUCE-IT study using post hoc analyses based upon smoking history. Groups were classified as never smokers (n=3264), former smokers (n=3672), and current smokers (n=1241). Results Compared with placebo, IPE use in combined current and former smokers (n=4913) was associated with significant reductions in time to the primary composite endpoint (hazard ratio, 0.77 [95% CI, 0.68–0.87]; P<0.0001) and in total events (rate ratio, 0.71 [95% CI, 0.61–0.82]; P<0.0001) (Figure 1). These benefits remained significant when subdivided into current and former smokers and were associated with reductions in the key secondary composite endpoint (P=0.04, P=0.005), and the individual components of CV death or nonfatal MI (P=0.04, P=0.01) and fatal or nonfatal MI (P=0.009, P=0.01, respectively). Never smokers also had a significant benefit from IPE for both the primary and key secondary endpoints. Overall, there were similar estimated rates of first occurrences of CV death, MI, stroke, coronary revascularisation, or hospitalisation for unstable angina in current smokers (23.8%) and former smokers (23.0%) assigned to IPE compared with never smokers on placebo (25.7%) (Figure 2). Conclusions In the REDUCE-IT study, IPE treatment significantly reduced the risk of CV events in current and former smokers to levels observed in never smokers. While smoking cessation should always be recommended, these data raise the possibility that IPE treatment may markedly attenuate the CV hazards attributable to smoking. Funding Acknowledgement Type of funding sources: None.

Cost-effectiveness of icosapent ethyl for primary and secondary cardiovascular prevention in the UK

Abstract Background Treatment with icosapent ethyl reduces the risk of major adverse cardiovascular events by 25% in patients with hypertriglyceridemia compared to placebo as demonstrated by The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT). Objective To assess the cost-effectiveness of icosapent ethyl, the purified eicosapentaenoic acid ethyl ester, in combination with statins compared to statin monotherapy for primary and secondary cardiovascular prevention from the perspective of England's National Health Service (NHS). Methods A Markov model simulated the progression of cardiovascular diseases and acute events, including myocardial infarction, stroke, angina, and coronary revascularization, in dyslipidaemia patients. The model was populated with cardiovascular outcome data derived from the REDUCE-IT trial. Cost and utility data were extracted from peer-reviewed literature. The incremental cost-effectiveness ratio (ICER) is reported per quality-adjusted life year (QALY) gained in 2021 Great Britain Pounds (£). Univariate, scenario, willingness-to-pay, and probabilistic sensitivity analyses were conducted to assess the robustness of results. Results For primary cardiovascular prevention, icosapent ethyl increased QALYs gained by 0.79 and costs by £15,421 compared to statin monotherapy (ICER: 19,485 £/QALY). For secondary prevention, the omega-3 fatty acid, icosapent ethyl, extended QALYs by 0.98 for patients at costs of £12,981 (ICER: 13,285 £/QALY). At the NHS' willingness-to-pay threshold of 25,000 £/QALY, there is 98% and 100% probability icosapent ethyl is cost-effective in primary and secondary prevention, respectively. Results remained robust under univariate, scenario, and probabilistic sensitivity analyses. Conclusion Icosapent ethyl is cost-effective for primary and secondary cardiovascular prevention at an annual price of £2,064 in the UK. Funding Acknowledgement Type of funding sources: None.

HIGH-INTENSITY STATINS COMBINED WITH EICOSAPENTAENOIC ACID (EPA) IMPROVES ENDOTHELIAL FUNCTION DURING EXPOSURE TO OXIDIZED LDL

BackgroundDuring atherosclerosis, endothelial cell (EC) dysfunction results in reduced nitric oxide (NO) bioavailability and increased cytotoxic peroxynitrite (ONOO−). This loss of NO bioavailability results in abnormal vasodilation and inflammatory changes. Eicosapentaenoic acid (EPA) administered as icosapent ethyl (IPE) reduced cardiovascular (CV) events in high-risk patients treated with statins (REDUCE-IT). We tested the effects of high-intensity statins and EPA in ECs exposed to oxidized LDL (oxLDL).Methods and ResultsHuman umbilical vein ECs (HUVECs) were pretreated with 20 mg/dL oxLDL for 20 min, then treated with atorvastatin (active metabolite, ATM) and rosuvastatin (rosuva) at 1.0 μM ± EPA (10μM) for 1 hr. Cells were stimulated with calcium and assayed for the NO/ONOO− release ratio using nanosensors. ECs exposed to oxLDL showed a 60% reduction in NO release compared with vehicle (386±29 to 156±18 nM, p< 0.001) concomitant with a pronounced increase in ONOO− release (205±31 to 283±16 nM, p< 0.001), resulting in a >70% decrease in the NO/ONOO− release ratio (p < 0.001). ECs treated with ATM had an improved NO/ONOO− release ratio (53%) that increased in combination with EPA by 216% (p < 0.01). Similar results were observed for EPA in combination with rosuvastatin. When either statin was combined with EPA, there was also decreased ONOO− release compared to statin alone (p < 0.01).ConclusionIn combination with high intensity statins, EPA enhanced NO bioavailability in dysfunctional human ECs. The ability of EPA to reverse vascular EC dysfunction may lead to reduced ischemic events in statin-treated patients, as evidenced in outcome trials. BackgroundDuring atherosclerosis, endothelial cell (EC) dysfunction results in reduced nitric oxide (NO) bioavailability and increased cytotoxic peroxynitrite (ONOO−). This loss of NO bioavailability results in abnormal vasodilation and inflammatory changes. Eicosapentaenoic acid (EPA) administered as icosapent ethyl (IPE) reduced cardiovascular (CV) events in high-risk patients treated with statins (REDUCE-IT). We tested the effects of high-intensity statins and EPA in ECs exposed to oxidized LDL (oxLDL). During atherosclerosis, endothelial cell (EC) dysfunction results in reduced nitric oxide (NO) bioavailability and increased cytotoxic peroxynitrite (ONOO−). This loss of NO bioavailability results in abnormal vasodilation and inflammatory changes. Eicosapentaenoic acid (EPA) administered as icosapent ethyl (IPE) reduced cardiovascular (CV) events in high-risk patients treated with statins (REDUCE-IT). We tested the effects of high-intensity statins and EPA in ECs exposed to oxidized LDL (oxLDL). Methods and ResultsHuman umbilical vein ECs (HUVECs) were pretreated with 20 mg/dL oxLDL for 20 min, then treated with atorvastatin (active metabolite, ATM) and rosuvastatin (rosuva) at 1.0 μM ± EPA (10μM) for 1 hr. Cells were stimulated with calcium and assayed for the NO/ONOO− release ratio using nanosensors. ECs exposed to oxLDL showed a 60% reduction in NO release compared with vehicle (386±29 to 156±18 nM, p< 0.001) concomitant with a pronounced increase in ONOO− release (205±31 to 283±16 nM, p< 0.001), resulting in a >70% decrease in the NO/ONOO− release ratio (p < 0.001). ECs treated with ATM had an improved NO/ONOO− release ratio (53%) that increased in combination with EPA by 216% (p < 0.01). Similar results were observed for EPA in combination with rosuvastatin. When either statin was combined with EPA, there was also decreased ONOO− release compared to statin alone (p < 0.01). Human umbilical vein ECs (HUVECs) were pretreated with 20 mg/dL oxLDL for 20 min, then treated with atorvastatin (active metabolite, ATM) and rosuvastatin (rosuva) at 1.0 μM ± EPA (10μM) for 1 hr. Cells were stimulated with calcium and assayed for the NO/ONOO− release ratio using nanosensors. ECs exposed to oxLDL showed a 60% reduction in NO release compared with vehicle (386±29 to 156±18 nM, p< 0.001) concomitant with a pronounced increase in ONOO− release (205±31 to 283±16 nM, p< 0.001), resulting in a >70% decrease in the NO/ONOO− release ratio (p < 0.001). ECs treated with ATM had an improved NO/ONOO− release ratio (53%) that increased in combination with EPA by 216% (p < 0.01). Similar results were observed for EPA in combination with rosuvastatin. When either statin was combined with EPA, there was also decreased ONOO− release compared to statin alone (p < 0.01). ConclusionIn combination with high intensity statins, EPA enhanced NO bioavailability in dysfunctional human ECs. The ability of EPA to reverse vascular EC dysfunction may lead to reduced ischemic events in statin-treated patients, as evidenced in outcome trials. In combination with high intensity statins, EPA enhanced NO bioavailability in dysfunctional human ECs. The ability of EPA to reverse vascular EC dysfunction may lead to reduced ischemic events in statin-treated patients, as evidenced in outcome trials.

INCREASED EICOSAPENTAENOIC ACID TO ARACHIDONIC ACID (EPA/AA) RATIO IN BRAIN ENDOTHELIAL CELLS ASSOCIATED WITH REDUCED EXPRESSION OF NEUTROPHIL DEGRANULATION PROTEINS DURING INFLAMMATION

Endothelial cell (EC) dysfunction results in inflammation and increased atherothrombotic risk, including stroke. The omega-3 fatty acid (FA) eicosapentaenoic acid (EPA) improves arterial compliance in a manner predicted by circulating EPA/AA ratios, an indicator of cardiovascular (CV) risk. Treatment with icosapent ethyl (IPE), a formulation of highly purified EPA, reduced composite CV events, including stroke, in REDUCE-IT that correlated with on-treatment EPA levels. We measured the effects of EPA on the EPA/AA ratio and protein expression in endothelial cells from brain ECs (BECs) following cytokine challenge.

EICOSAPENTAENOIC ACID (EPA) DECREASES CYTOKINE RELEASE AND EXPRESSION OF INFLAMMATORY AND PRO-THROMBOTIC PROTEINS IN BRAIN VASCULAR ENDOTHELIUM

Brain vascular endothelial cell (EC) dysfunction contributes to ischemic stroke due to inflammation and release of pro-thrombotic factors. Treatment with icosapent ethyl (IPE), the ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid (EPA), reduced first and total ischemic strokes each by 36%, in statin-treated patients with elevated cardiovascular risk (REDUCE-IT). We tested the effects of EPA on cytokine release and expression of inflammatory proteins from brain microvascular ECs during inflammation.

TREATMENT IMPLICATIONS OF THE REDUCE-IT RESULTS TO PEOPLE OF SOUTH ASIAN (SA) DESCENT LIVING IN CANADA WITH KNOWN ATHEROSCLEROTIC CARDIOVASCULAR DISEASE(THE REDUCE-IT CANADA SA STUDY)

The REDUCE-IT trial demonstrated that icosapent ethyl (IPE), a highly purified eicosapentaenoic acid ethyl ester, lowers cardiovascular (CV) events and CV death in statin-treated individuals with mild-moderate hypertriglyceridemia, relatively well-controlled low-density lipoprotein cholesterol (LDL-C) levels and with either known CV disease or diabetes with other risk factors. Inasmuch as over 90% of the REDUCE-IT cohort were White, the generalization of its results to non-White populations is unclear.

EVALUATION OF THE REAL-WORLD PLACE OF THE ICOSAPENT ETHYL (IPE) FOR THE TREATMENT OF PATIENTS WITH HYPERTRIGLYCERIDEMIA REQUIRING INVASIVE CORONARY ANGIOGRAM

Although the REDUCE-IT trial recently demonstrated the benefits of Icosapent ethyl (IPE) on reducing ischemic events in a broad population of primary and secondary prevention patients with hypertriglyceridemia, its generalizability to patients referred for a coronary angiogram is not known yet. This study aims to determine the proportion of patients referred for a coronary angiogram that would be eligible for IPE treatment.

Proposing Vascepa (Icosapent Ethyl) as Supplemental Treatment Targeting the Underlying Causes of Persistent, Post-Viral Symptoms Associated with COVID-19: A Case Series

Current treatment options of post-viral COVID-19 symptoms lack conclusive evidence of success in infected individuals, leaving a desperate need for alternative treatments. In this study, we propose the use of icosapent ethyl (IPE), a pure esterized form of omega-3 fatty acid eicosapentaenoic acid (EPA), for its current use as a cell membrane stabilizer, anti-inflammatory and antithrombotic agent. This case series consists of patients, all of which experienced persistent post-viral symptoms of COVID-19 weeks to months after incidence of infection. Each patient reported considerable improvement of various COVID-19 symptoms including post-exertional malaise, cognitive impairment, and dermatologic complaints, primarily hair loss and onycholysis. As a result, we believe each of these individual outcomes collectively provide a starting point in demonstrating the potential success of IPE in treating persistent COVID-19 symptoms brought on by systemic hyperinflammation and hypercoagulation. In doing so, we hope to spark additional research detailing clinical outcomes of IPE administration to treat COVID-19.

Should we continue to subsidise therapeutics with uncertain efficacy? Health economic implications for icosapent ethyl.

Should we continue to subsidise therapeutics with uncertain efficacy? Health economic implications for icosapent ethyl.

Contemporary National Patterns of Eligibility and Use of Novel Lipid-Lowering Therapies in the United States.

Background The emergence of PCSK9i (proprotein convertase subtilisin kexin type 9 inhibitor) and icosapent ethyl (IPE) has expanded the role of lipid-lowering therapies beyond statins. Despite recommendations by clinical practice guidelines, their national eligibility and use rates remain unclear. Methods and Results In the National Health and Nutrition Examination Survey data from 2017 to 2020, we assessed eligibility and the use of statins, PCSK9i, and IPE among US adults according to American College of Cardiology/American Heart Association guideline recommendations. Eligibility for PCSK9i and IPE were determined in the following 2 scenarios: (1) assuming existing lipid-lowering therapy as the maximum tolerated before assessing eligibility for novel therapies and (2) assessing eligibility after assuming initiation and maximal escalation of preexisting lipid-lowering therapies and accounting for expected lipid improvements. Of 2729 sampled individuals, representing 149.3million adults, 1376 had indications for statins, representing 65.8million or 44.0% (95% CI, 40.9%-47.2%) of adults. Current statin use was 45% of those eligible and was low across demographic groups. A total of 9.7 and 11.6million adults would benefit from PCSK9i and IPE, respectively, based on lipid profiles and existing therapies. Assuming maximal escalation of statins and addition of ezetimibe, 4.1% (95% CI, 2.8%-5.4%) of adults or 6.1million would benefit from PCSK9i and 6.8% (95% CI, 5.4%-8.3%) or 10.2million from IPE. Conclusions Six and 10 million individuals have clinical profiles whereby PCSK9i and IPE, respectively, would be expected to improve cardiovascular outcomes even after maximum escalation of statins and ezetimibe use, but remain undertreated with lipid-lowering therapies. Optimal use of lipid-targeted agents that include these novel agents is needed to improve population health outcomes.

Long-term safety and efficacy of MND-2119 (self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester) in patients with hypertriglyceridemia: Results from a multicenter, 52-week, open-label study

BackgroundIn Japan, eicosapentaenoic acid ethyl ester (EPA-E) is administered twice-daily or three-times-daily for dyslipidemia. We have developed MND-2119, a novel self-emulsifying formulation of highly purified EPA-E which can be administered once-daily. ObjectiveThe objective of this study was to investigate the safety and efficacy of long-term administration of MND-2119 in hypertriglyceridemia patients. MethodsIn this multicenter, 52-week, open-label study, patients with high triglyceride (TG) (TG levels between ≥ 150 and < 500 mg/dL) undergoing lifestyle modification were randomized to MND-2119 2 g/day (n=61) or MND-2119 4 g/day (n=61). ResultsThe incidence of adverse events in MND-2119 2 g/day and MND-2119 4 g/day was 70.5% and 62.3%, respectively, and the incidence of adverse drug reactions was 9.8% and 8.2%, respectively. There were no notable problems in the safety assessments of both treatment groups. By Week 4, TG levels had decreased from baseline in both groups, and the TG reducing effect continued up to Week 52 (mean percentage change from baseline in TG at Week 52 [two-sided 95% confidence interval]: MND-2119 2 g/day: -16.71% [-26.61, -6.81], MND-2119 4 g/day: -21.01% [-27.86, -14.16]). In both groups, plasma EPA concentration at Week 4 was maintained up until Week 52 and the plasma EPA concentration at Week 52 was 200.5 ± 54.7 μg/mL in MND-2119 2 g/day and 308.6 ± 98.6 μg/mL in MND-2119 4 g/day. ConclusionLong-term administration of MND-2119 was not associated with any safety-related problems. TG levels decreased by Week 4, and the TG reducing effect continued up to Week 52.

Under-reporting and under-representation of non-Hispanic Black subjects in lipid-lowering atherosclerotic cardiovascular disease outcomes trials: A systematic review

BackgroundNon-Hispanic (NH) Black participants have been under-represented in studies of cardiovascular disease. ObjectiveWe sought to determine the trends of reporting and representation of NH Black subjects in randomized controlled trials (RCTs) of lipid-lowering therapies demonstrating atherosclerotic cardiovascular disease (ASCVD) risk reduction benefit. MethodsThe electronic databases of MEDLINE, EMBASE and ClinicalTrials.gov were searched from 1990-2020. Studies of lipid-lowering therapies (i.e., statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9], and icosapent ethyl) with proven ASCVD benefit, sample sizes of at least 1000 subjects and follow-up of at least 1 year were included (40 RCTs, N=306 747 total participants). We examined articles and supplementary material for participant-level race data. Using United States disease prevalence data, the participation-to-prevalence ratio (PPR) metric was used to estimate the representation of NH Black subjects compared with their reported disease burden (i.e., < 0.8 indicated under-representation; > 1.2, over-representation; and 0.8 to <1.2, adequate representation). ResultsThe median (interquartile range) number of participants per trial was 4871 (2434-10077). NH Black enrollees comprised 7.3% (95% CI, 0.9%-15.4%) of the total number of subjects reported. During the time intervals 1990-1995, 1996-2000, 2001-2005, 2006-2010, 2011-2015 and 2016-2020, NH Black participation was 0%, 1.1%, 4.4%, 4.8%, 0.2% and 0.7% respectively (P for trend <0.001). For statin trials, the participation of NH Black subjects was reported in 0 studies between 1990-1995 and in 9 of 28 trials from 1996-2020. For ezetimibe and icosapent ethyl, NH Black participants were reported in 0 of 3 and 0 of 1 studies, respectively. For trials of PCSK9 inhibitors, NH Black subjects were reported in 2 of 5 (40%). NH Black participants were under-represented compared with their disease burden in studies evaluating subjects with diabetes, hypercholesterolemia, stable coronary artery disease, and acute coronary syndrome (PPR < 0.8 for all). ConclusionNH Black participants are markedly under-represented, and results are under-reported. The inclusion of population and disease specific representation of NH Black persons and their related social determinants of health will help to address the disparity in preventive care for this historically undertreated population.

Hypertriglyceridemia-Induced Acute Pancreatitis During Pregnancy: A Case Report

Hypertriglyceridemia-induced acute pancreatitis is a rare and serious condition that places both the mother and the fetus at severe risk for morbidity and mortality. The goal of this case report is to describe the management of a pregnant patient with severely elevated triglycerides in the setting of acute pancreatitis. A 28-year-old female G2P1001 at 29 weeks of gestational age presented with epigastric abdominal pain. A computed tomography scan of the abdomen and pelvis with contrast demonstrated acute interstitial edematous pancreatitis. A lipid panel was performed, revealing a serum triglyceride level of 3,949 mg/dL. Insulin and maternal bowel rest reduced her serum triglyceride levels; however, additional medical therapy including fibrate and statin drugs were initiated to achieve goal levels of triglycerides and improve patient symptoms. The patient ultimately recovered and remained on treatment until delivery. Initial management addresses acute pancreatitis and involves fluid resuscitation, pain control, and bowel rest. Triglyceride-lowering drug therapies are rarely used during pregnancy due to the potential for fetal teratogenicity; however, given the severity of hypertriglyceridemia fenofibrate and atorvastatin were prescribed. Additional medical treatment included insulin, omega-3, and ethyl eicosapentaenoic acid.

Huntington’s Disease: current therapies and future directions

Huntington’s disease is a neurodegenerative disease that have significantly negative impact to cognitive function. In the worldwide range, approximately 5-10 individuals are affected per 100,000 people. At molecular level, the expanded CAG repeats lead to misfolding and aggregation of the huntington protein, which can interfere with cellular metabolism, including transcription, mitochondrial function, and other important physiological processes. Though scientists already have a well-established theory for the pathology of Huntington’s Disease, no effected cure has been developed due to the heavy genetic base of the disease. Despite the genetic barrier to overcome, many therapies have been created to alleviate the symptoms. In this primer, four main therapies are discussed who reduce the mutant huntington protein amount at post-transcriptional level: Antisense Oligonucleotides, Ethyl-Eicosapentaenoic Acid, autophagy modification, and intrabody based immunotherapy. Within each module, it is described how these therapies can reduce the level of mHTT in molecular level and correct the symptom. Development history is also touched upon briefly and discussion about the current status of each approach is made. Clinical prospective and future direction is included at the end as well.

Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy.

REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) reported a 25% relative risk reduction in major adverse cardiovascular events with use of icosapent ethyl compared with pharmaceutical grade mineral oil. The mechanisms underlying this benefit remain uncertain. We explored whether treatment allocation in REDUCE-IT might affect a series of biomarkers in pathways known to associate with atherosclerosis risk. Serum levels of interleukin-1β, interleukin-6, high-sensitivity C-reactive protein, oxidized low-density lipoprotein cholesterol, homocysteine, lipoprotein(a), and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured at baseline, at 12 months, at 24 months, and at the end-of-study visit among REDUCE-IT participants with triglyceride levels ≥135 mg/dL and <500 mg/dL who were randomly allocated to treatment with either 4 grams daily of icosapent ethyl or mineral oil used as a comparator. At baseline, median levels of each biomarker were similar in the 2 treatment groups. The levels of biomarkers associated with atherosclerosis increased over time among those allocated to mineral oil treatment; in this group at 12 months, the median percent increases from baseline were 1.5% for homocysteine, 2.2% for lipoprotein(a), 10.9% for oxidized low-density lipoprotein cholesterol, 16.2% for interleukin-6, 18.5% for lipoprotein-associated phospholipase A2, 21.9% for high-sensitivity C-reactive protein, and 28.9% for interleukin-1β (all P values <0.001), with similar changes at 24 months. In the icosapent ethyl group, there were minimal changes in these biomarkers at 12 and 24 months. As such, at study conclusion, between-group treatment differences largely reflected increases in the mineral oil group with median percent differences of 2.4% for lipoprotein(a), 3.0% for homocysteine, 4.2% for oxidized low-density lipoprotein cholesterol, 19.8% for interleukin-6, 26.2% for Lp-PLA2, 38.5% for high-sensitivity C-reactive protein, and 48.7% for interleukin-1β (all P values ≤0.007). These data are consistent with previous REDUCE-IT results in which the median percent change for low-density lipoprotein cholesterol at 12 months was -1.2% among those allocated to icosapent ethyl and 10.9% among those allocated to the mineral oil comparator. Among participants in REDUCE-IT, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas levels increased among those allocated to mineral oil. The effect of these findings on interpretation of the overall risk reductions in clinical events observed within REDUCE-IT is uncertain. URL: https://www. gov; Unique identifier: NCT01492361.