Adapalene induces adipose browning through the RARß-p38 MAPK-ATF2 pathway.

Adipose browning has recently been reported to be a novel therapeutic strategy for obesity. Because the retinoic acid receptor (RAR) is a potential target involved in browning, adapalene (AD), an anti-acne agent with RAR agonism, was examined in detail for its effects on adipose browning and the underlying mechanisms in vitro and in vivo. AD upregulated the expression of adipose browning-related markers in a concentration-dependent manner, promoted mitochondrial biogenesis, increased oxygen consumption rates, and lowered lipid droplet sizes in differentiated 3T3/L1 white adipocytes. Among the three retinoic acid receptors (RARα, RARß, and RARγ), knockdown of the gene encoding RARß mitigated AD-induced adipose browning. Similarly, LE135 (a selective RARß antagonist) attenuated AD action, suggesting that AD promotes adipose browning through RARß. Sequential phosphorylation of p38 mitogen-activated protein kinase (MAPK) and activating transcription factor 2 (ATF2) was critical for AD-induced adipose browning, based on the observations that either SB203580 (a p38 MAPK inhibitor) or ATF2 siRNA reduced the effects of AD. In vivo browning effects of AD were confirmed in C57BL/6J mice and high-fat diet-induced obese (DIO) mice after oral administration of AD either acutely or chronically. This study identifies new actions of AD as an adipose browning agent and demonstrates that RARß activation followed by increased phosphorylation of p38 MAPK and ATF2 appears to be a key mechanism of AD action.

Inhibition of STAT3 enhances UCP1 expression and mitochondrial function in brown adipocytes.

Extensive studies have shown that the increasing brown adipose tissue (BAT) mass/activity possesses a strong ability to prevent obesity and its related complications. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signal pathway is known to play a role in adipocyte differentiation and development. However, its impact on thermogenic properties of mature brown adipocytes has not yet been clarified. Nifuroxazide (NFX), a potent inhibitor of STAT3, has received widespread attention due to its alternative anti-tumor and anti-inflammatory effects. Herein, we report that NFX induces lipolysis with subsequent downregulation of ACCα and FAS, while ATGL and pHSL levels are elevated in mature brown adipocytes. Furthermore, NFX treatment promotes the mitochondrial respiration of mature brown adipocytes, as evidenced by increased expression of thermogenic transcriptional factors and mitochondrial content. In addition, it also alleviates the IL-6 and TNFα inhibition on brown thermogenic programming via suppressing the STAT3/NF-κB/IL-6 signaling pathway. In general, these findings suggest that the blockade of the JAK/STAT3 pathway by NFX has a pro-thermogenic effect on mature brown adipocytes which opens new perspectives for NFX repurposing and potential therapeutic route to counteract obesity and related metabolic disorders.

Icosapent ethyl: safely reducing cardiovascular risk in adults with elevated triglycerides.

INTRODUCTION: In patients at high cardiovascular risk, the rate of events remains elevated despite traditional, evidence-based lipid-lowering therapy. Residual hypertriglyceridemia is an important contributor to this risk. However, prior medications with triglyceride-lowering effects have not reduced adverse clinical outcomes in the statin era. AREAS COVERED: The present review summarizes evidence and recommendations related to triglyceride-lowering therapy in the primary and secondary preventive settings. We provide an overview of findings from recent meta-analyses, important observational studies, and a detailed description of landmark trials, including the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT). We further review recommendations from current guidelines. EXPERT OPINION: Icosapent ethyl is a stable, highly purified ethyl ester of eicosapentaenoic acid that safely and effectively reduces cardiovascular events in the contemporary setting. It is prescribed at a dose of 2 grams twice daily and is indicated in patients at high cardiovascular risk who have fasting or non-fasting triglyceride levels ≥150 mg/dl despite maximally tolerated statin treatment, or in individuals with triglyceride levels ≥500 mg/dl. Conversely, omega-3 fatty acid preparations containing a combination of eicosapentaenoic acid and docosahexaenoic acid are not indicated for reduction of cardiovascular risk and should be actively deprescribed.

Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT.

BACKGROUND: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE. OBJECTIVES: The purpose of this study was to determine the effects of IPE on investigator-reported events. METHODS: Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance. RESULTS: There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints. CONCLUSIONS: IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).

Familial Hypercholesterolemia: JACC Focus Seminar 4/4.

Detecting familial hypercholesterolemia (FH) early and "normalizing" low-density lipoprotein (LDL) cholesterol values are the 2 pillars for effective cardiovascular disease prevention in FH. Combining lipid-lowering therapies targeting synergistic/complementary metabolic pathways makes this feasible, even among severe phenotypes. For LDL receptor-dependent treatments, PCSK9 remains the main target for adjunctive therapy to statins and ezetimibe through a variety of approaches. These include protein inhibition (adnectins), inhibition of translation at mRNA level (antisense oligonucleotides or small interfering RNA), and creation of loss-of-function mutations through base-pair editing. For patients with little LDL receptor function, LDL receptor-independent treatment targeting ANGPTL3 through monoclonal therapies are now available, or in the future, antisense/small interfering RNA-based approaches offer alternative approaches. Finally, first-in-human studies are ongoing, testing adenovirus-mediated gene therapy transducing healthy LDLR DNA in patients with HoFH. Further development of the CRISPR cas technology, which has shown promising results in vivo on introducing PCSK9 loss-of-function mutations, will move a single-dose, curative treatment for FH closer.

Investigating Lipid-Modulating Agents for Prevention or Treatment of COVID-19: JACC State-of-the-Art Review.

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management.

Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study.

BACKGROUND: AMP kinase (AMPK) is an energy sensor implicated in regulation of lipid metabolism, inflammation, and insulin sensitivity. We aimed to assess efficacy and safety of PXL770, a novel direct AMPK activator, in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: STAMP-NAFLD, a randomised, double-blind, placebo-controlled phase 2a study, was done across 15 US clinical sites. Patients aged 18-75 years with liver fat content of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned (1:1:1:1), via an interactive web response system, to receive oral PXL770 250 mg once daily, 250 mg twice daily, or 500 mg once daily, or matched placebo. Patients were stratified according to type 2 diabetes status and study site. The primary endpoint was relative change in liver fat content from baseline compared with placebo at week 12, assessed by MRI-PDFF. The primary endpoint was analysed in an ANCOVA model with treatment and stratification criteria as factors and baseline liver fat content as a covariate in the modified intention-to-treat population, defined as all as-randomised patients who received at least one dose of study treatment. Safety was analysed in the safety population, defined as all as-treated patients receiving at least one dose of the study treatment. The trial has been completed and the final results are reported. The trial is registered with ClinicalTrials.gov, NCT03763877. FINDINGS: Between March 29, 2019, and March 13, 2020, 387 patients were screened, of whom 120 were included in the modified intention-to-treat and safety analyses (30 in the 250 mg once daily group, 30 in the 250 mg twice daily group, 29 in the 500 mg once daily group, and 31 in the placebo group). The mean relative change from baseline in liver fat content at week 12 was -1·1% in the placebo group, -1·0% in the 250 mg once daily group (mean difference versus placebo 0·1% [95% CI -15·4 to 15·7], p=0·99), -14·3% in the 250 mg twice daily group (-13·1% [-28·1 to 1·8], p=0·084), and -14·7% in the 500 mg once daily group (-13·5% [-28·5 to 1·4], p=0·076). At least one treatment-emergent adverse event occurred in 23 (77%) of 30 patients in the 250 mg once daily group, 20 (67%) of 30 patients in the 250 mg twice daily group, 21 (72%) of 29 patients in the 500 mg once daily group, and 21 (68%) of 31 patients in the placebo group. The most common treatment-emergent adverse event was diarrhoea (five [17%] of patients in the 250 mg once daily group, seven [23%] in the 250 mg twice daily group, six [21%] in the 500 mg once daily group, and none in the placebo group). No life-threatening events or treatment-related deaths occurred. INTERPRETATION: PXL770 treatment did not meet the primary outcome of liver fat improvement compared with placebo. Treatment was well tolerated. Given indications that metabolic features improved with PXL770 treatment, AMPK activation might be a promising pharmacological target for patients with type 2 diabetes and NAFLD, and could also be considered for further assessment in patients with non-alcoholic steatohepatitis. FUNDING: Poxel.

Using Consistently Low Performance to Identify Low-Quality Physician Groups.

Importance: There has been a growth in the use of performance-based payment models in the past decade, but inherently noisy and stochastic quality measures complicate the assessment of the quality of physician groups. Examining consistently low performance across multiple measures or multiple years could potentially identify a subset of low-quality physician groups. Objective: To identify low-performing physician groups based on consistently low performance after adjusting for patient characteristics across multiple measures or multiple years for 10 commonly used quality measures for diabetes and cardiovascular disease (CVD). Design, Setting, and Participants: This cross-sectional study used medical and pharmacy claims and laboratory data for enrollees ages 18 to 65 years with diabetes or CVD in an Aetna health insurance plan between 2016 and 2019. Each physician group's risk-adjusted performance for a given year was estimated using mixed-effects linear probability regression models. Performance was correlated across measures and time, and the proportion of physician groups that performed in the bottom quartile was examined across multiple measures or multiple years. Data analysis was conducted between September 2020 and May 2021. Exposures: Primary care physician groups. Main Outcomes and Measures: Performance scores of 6 quality measures for diabetes and 4 for CVD, including hemoglobin A1c (HbA1c) testing, low-density lipoprotein testing, statin use, HbA1c control, low-density lipoprotein control, and hospital-based utilization. Results: A total of 786 641 unique enrollees treated by 890 physician groups were included; 414 655 (52.7%) of the enrollees were men and the mean (SD) age was 53 (9.5) years. After adjusting for age, sex, and clinical and social risk variables, correlations among individual measures were weak (eg, performance-adjusted correlation between any statin use and LDL testing for patients with diabetes, r = -0.10) to moderate (correlation between LDL testing for diabetes and LDL testing for CVD, r = .43), but year-to-year correlations for all measures were moderate to strong. One percent or fewer of physician groups performed in the bottom quartile for all 6 diabetes measures or all 4 cardiovascular disease measures in any given year, while 14 (4.0%) to 39 groups (11.1%) were in the bottom quartile in all 4 years for any given measure other than hospital-based utilization for CVD (1.1%). Conclusions and Relevance: A subset of physician groups that was consistently low performing could be identified by considering performance measures across multiple years. Considering the consistency of group performance could contribute a novel method to identify physician groups most likely to benefit from limited resources.

Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition.

Animal African Trypanosomiasis (AAT) is a debilitating livestock disease prevalent across sub-Saharan Africa, a main cause of which is the protozoan parasite Trypanosoma congolense. In comparison to the well-studied T. brucei, there is a major paucity of knowledge regarding the biology of T. congolense. Here, we use a combination of omics technologies and novel genetic tools to characterise core metabolism in T. congolense mammalian-infective bloodstream-form parasites, and test whether metabolic differences compared to T. brucei impact upon sensitivity to metabolic inhibition. Like the bloodstream stage of T. brucei, glycolysis plays a major part in T. congolense energy metabolism. However, the rate of glucose uptake is significantly lower in bloodstream stage T. congolense, with cells remaining viable when cultured in concentrations as low as 2 mM. Instead of pyruvate, the primary glycolytic endpoints are succinate, malate and acetate. Transcriptomics analysis showed higher levels of transcripts associated with the mitochondrial pyruvate dehydrogenase complex, acetate generation, and the glycosomal succinate shunt in T. congolense, compared to T. brucei. Stable-isotope labelling of glucose enabled the comparison of carbon usage between T. brucei and T. congolense, highlighting differences in nucleotide and saturated fatty acid metabolism. To validate the metabolic similarities and differences, both species were treated with metabolic inhibitors, confirming that electron transport chain activity is not essential in T. congolense. However, the parasite exhibits increased sensitivity to inhibition of mitochondrial pyruvate import, compared to T. brucei. Strikingly, T. congolense exhibited significant resistance to inhibitors of fatty acid synthesis, including a 780-fold higher EC50 for the lipase and fatty acid synthase inhibitor Orlistat, compared to T. brucei. These data highlight that bloodstream form T. congolense diverges from T. brucei in key areas of metabolism, with several features that are intermediate between bloodstream- and insect-stage T. brucei. These results have implications for drug development, mechanisms of drug resistance and host-pathogen interactions.

Lipid droplet: A functionally active organelle in monocyte to macrophage differentiation and its inflammatory properties.

Lipid droplets (LDs) perform several important functions like inflammatory responses, membrane trafficking, acts as secondary messengers, etc. rather than simply working as an energy reservoir. LDs have been implicated as a controlling factor in the progression of atherosclerosis followed by foam cell formation that derives from macrophages during the differentiation process. However, the role of LDs in monocyte differentiation or its further immunological function is still an area that mandates in-depth investigation. We report that LD dynamics is important for differentiation of monocytes and is absolutely required for sustained and prolonged functional activity of differentiated macrophages. In THP-1 cell line model system, we elucidated that increase in total LD content in monocyte by external lipid supplements, can induce monocyte differentiation independent of classical stimuli, PMA. Differential expression of PLIN2 and ATGL during the event, together with abrogation of de novo lipogenesis further confirmed the fact. Besides, an increase in LD content by free fatty acid supplement was able to exert a synergistic effect with PMA on differentiation and phagocytic activity compared to when they are used alone. Additionally, we have shown Rab5a to play a vital role in LDs biosynthesis/maturation in monocytes and thereby directly affecting differentiation of monocytes into macrophages via AKT pathway. Thus our study reveals the multi-faceted function of LDs during the process of monocyte to macrophage differentiation and thereby helping to maintain the functional activity.

Drug Adherence and Long-Term Outcomes in Non-Revascularized Patients Following Acute Myocardial Infarction.

This study examined long-term outcomes and adherence to guideline-based medications in non-revascularized acute myocardial infarction (MI) patients undergoing and not undergoing angiography. We analyzed non-revascularized MI patients hospitalized in Alberta, Canada between 2010-2016 and categorized them according to whether they had undergone coronary angiography. Adherence to guideline-based medications was determined by the proportion of days covered (PDC) and subdivided into categories based on PDC: 0% (none), 1-40% (low), 40-79% (intermediate) and ≥ 80% (high). Patients not undergoing angiography were older, less frequently male, and had more comorbidities. Those not receiving angiography had higher rates of 2-year myocardial infarction (9.9% vs 6.1%, p <0.001), heart failure (14.9% vs 6.1%, p <0.001), and mortality (29.4% vs 7.4%, p <0.001). Optimal medial therapy (OMT), defined by high PDC for the combination of lipid-modifying agents, ß-blockers and angiotensin converting enzyme-inhibitors/receptor blockers (ACE-I/ARBs), was achieved in 32.9%. Patients not undergoing angiography had lower rates of OMT adherence (p <0.001). In patients not undergoing angiography, high-adherence to lipid-modifying agents (HR 0.70 [95% CI 0.57-0.87]), ß-blockers (HR 0.78 [0.62-0.97]), ACE-I/ARBs (HR 0.64 [0.52-0.79]) and OMT (HR 0.56 [0.40-0.77]) was independently associated with lower 2-year mortality. In conclusion, MI patients not receiving angiography had low adherence rates to guideline-based pharmacotherapies and high rates of long-term outcomes, suggesting potential treatment targets to improve prognosis in non-invasively managed MI patients.

Lipoprotein(a) is robustly associated with aortic valve calcium.

OBJECTIVES: To investigate the prevalence and quantity of aortic valve calcium (AVC) in two large cohorts, stratified according to age and lipoprotein(a) (Lp(a)), and to assess the association between Lp(a) and AVC. METHODS: We included 2412 participants from the population-based Rotterdam Study (52% women, mean age=69.6±6.3 years) and 859 apparently healthy individuals from the Amsterdam University Medical Centers (UMC) outpatient clinic (57% women, mean age=45.9±11.6 years). All individuals underwent blood sampling to determine Lp(a) concentration and non-enhanced cardiac CT to assess AVC. Logistic and linear regression analyses were performed to investigate the associations of Lp(a) with the presence and amount of AVC. RESULTS: The prevalence of AVC was 33.1% in the Rotterdam Study and 5.4% in the Amsterdam UMC cohort. Higher Lp(a) concentrations were independently associated with presence of AVC in both cohorts (OR per 50 mg/dL increase in Lp(a): 1.54 (95% CI 1.36 to 1.75) in the Rotterdam Study cohort and 2.02 (95% CI 1.19 to 3.44) in the Amsterdam UMC cohort). In the Rotterdam Study cohort, higher Lp(a) concentrations were also associated with increase in aortic valve Agatston score (ß 0.19, 95% CI 0.06 to 0.32 per 50 mg/dL increase). CONCLUSIONS: Lp(a) is robustly associated with presence of AVC in a wide age range of individuals. These results provide further rationale to assess the effect of Lp(a) lowering interventions in individuals with early AVC to prevent end-stage aortic valve stenosis.

Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges.

Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk of coronary heart disease and stroke. Guidelines for the management of dyslipidaemia from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) were updated in late 2019 in light of recent intervention trials involving the use of innovative lipid-lowering agents in combination with statins. The new guidelines advocate achieving very low LDL-C levels in individuals at highest risk, within the paradigm of 'lower is better'. With the advent of combination therapy using ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitors in addition to statins, the routine attainment of extremely low LDL-C levels in the clinic has become a reality. Moreover, clinical trials in this setting have shown that, over the 5-7 years of treatment experience to date, profound LDL-C lowering leads to further reduction in cardiovascular events compared with more moderate lipid lowering, with no associated safety concerns. These reassuring findings are bolstered by genetic studies showing lifelong very low LDL-C levels (<1.4 mmol/L; <55 mg/dL) are associated with lower cardiovascular risk than in the general population, with no known detrimental health effects. Nevertheless, long-term safety studies are required to consolidate the present evidence base. This review summarises key data supporting the ESC/EAS recommendation to reduce markedly LDL-C levels, with aggressive goals for LDL-C in patients at highest risk, and provides expert opinion on its significance for clinical practice.

Icosapent ethyl: scientific and legal controversies.

Icosapent ethyl (Vascepa) is a purified preparation of the omega-3 fatty acid eicosapentaenoic acid, which is marketed by Amarin Pharma based in Ireland. The product was initially approved by the US Food and Drug Administration for the use of a high dose (4 g/day) in the treatment of hypertriglyceridaemia. On the basis of the results of the REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl Intervention Trial), the agency later granted a label extension to include the additional indication of a reduction in risk of cardiovascular events in persons with serum triglyceride levels of 150 mg/dL or greater and established cardiovascular disease or diabetes. Data supporting the efficacy of omega-3 fatty acids in the prevention of cardiovascular disease have been inconsistent and controversial. The story of the development of icosapent ethyl has been fraught with challenges, including the invalidation of six core patents on the product, and recently, the completion of a new clinical trial, STRENGTH (Long-Term Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia), that directly contradicts REDUCE-IT and calls into question whether icosapent ethyl is actually effective in the secondary prevention of cardiovascular events. This article traces the course of the development of this fascinating product and discusses its complex medical, regulatory and legal history, which is still continuing to unfold.

Homozygous Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is an inherited disorder with retarded clearance of plasma LDL caused by mutations of the genes involved in the LDL receptor-mediated pathway and most of them exhibit autosomal dominant inheritance. Homozygotes of FH (HoFH) may have plasma LDL-C levels, which are at least twice as high as those of heterozygous FH (HeFH) and therefore four times higher than normal levels. Prevalence of HoFH had been estimated as 1 in 1,000,000 before but more recent genetic analysis surveys predict 1 in 170,000 to 300,000. Since LDL receptor activity is severely impaired, HoFH patients do not or very poorly respond to medications to enhance activity, such as statins, and have a poorer prognosis compared to HeFH. HoFH should therefore be clinically distinguished from HeFH. Thorough family studies and genetic analysis are recommended for their accurate diagnosis.Fatal cardiovascular complications could develop even in the first decade of life for HoFH, so aggressive lipid-lowering therapy should be initiated as early as possible. Direct removal of plasma LDL by lipoprotein apheresis has been the principal measure for these patients. However, this treatment alone may not achieve stable LDL-C target levels and combination with drugs should be considered. The lipid-lowering effects of statins and PCSK9 inhibitors substantially vary depending on the remaining LDL receptor activity of individual patients. On the other hand, the action an MTP inhibitor is independent of LDL receptor activity, and it is effective in most HoFH cases.This review summarizes the key clinical issues of HoFH as well as insurance coverage available under the Japanese public healthcare system.

EPA's pleiotropic mechanisms of action: a narrative review.

Treatment with icosapent ethyl 4 g/day, a highly purified and stable ethyl ester of eicosapentaenoic acid (EPA), demonstrated a significant reduction in atherosclerotic cardiovascular disease (ASCVD) events and death in REDUCE-IT. However, analyses of REDUCE-IT and meta-analyses have suggested that this clinical benefit is greater than can be achieved by triglyceride reduction alone. EPA therefore may have additional pleiotropic effects, including anti-inflammatory and anti-aggregatory mechanisms. EPA competes with arachidonic acid for cyclooxygenase and lipoxygenase, producing anti-inflammatory and anti-aggregatory metabolites rather than the more deleterious metabolites associated with arachidonic acid. Changing the EPA:arachidonic acid ratio may shift metabolic status from pro-inflammatory/pro-aggregatory to anti-inflammatory/anti-aggregatory. EPA also has antioxidant effects and increases synthesis of nitric oxide. Incorporation of EPA into phospholipid bilayers influences membrane structure and may help to prevent cardiac arrhythmias. Clinically, this may translate into improved vascular health, including regression of atherosclerotic plaque. Overall, EPA has a range of pleiotropic effects that contribute to a reduction in ASCVD.

Mechanistic Insights from REDUCE-IT STRENGTHen the Case Against Triglyceride Lowering as a Strategy for Cardiovascular Disease Risk Reduction.

Elevated triglyceride (TG) levels have been linked to residual atherosclerotic cardiovascular risk in patients with controlled low-density lipoprotein cholesterol. However, outcome trials testing TG-lowering agents have failed to demonstrate cardiovascular risk reduction in statin-treated subjects. One such example is the recent STRENGTH trial, which tested mixed omega fatty acids (n3-FAs, 4 g/d) in high-risk patients with elevated TGs. Similar to trials using fibrates and niacin, the STRENGTH trial failed despite effective TG lowering. Results from these studies have contributed to skepticism about the use of TG-lowering therapy for cardiovascular risk. However, new mechanistic insights are provided by the REDUCE-IT trial that used icosapent ethyl (IPE), a purified formulation of the n3-FA eicosapentaenoic acid. In high-risk patients, IPE reduced a composite of cardiovascular events (25%, P < .001) in a manner not predicted by TG lowering. Benefits with IPE appear linked to broad pleiotropic actions associated with on-treatment eicosapentaenoic acid levels. These studies indicate that although TGs are a potential biomarker of cardiovascular risk, there is no evidence that TG lowering itself is an effective strategy for reducing such risk.