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In this multicenter, placebo-controlled trial involving statin-treated patients with hypertriglyceridemia, the risk of ischemic events, including cardiovascular death, was significantly lower with 2 g of icosapent ethyl twice daily than with placebo.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can exert antidepressant, anti-inflammatory and neuroprotective properties, but the exact molecular mechanism underlying their effects is still not fully understood. We conducted both in vitro and clinical investigations to test which EPA or DHA metabolites are involved in these anti-inflammatory, neuroprotective and antidepressant effects. In vitro, we used the human hippocampal progenitor cell line HPC0A07/03C, and pre-treated cells with either EPA or DHA, followed by interleukin 1beta (IL1β), IL6 and interferon-alpha (IFN-α). Both EPA and DHA prevented the reduction in neurogenesis and the increase in apoptosis induced by these cytokines; moreover, these effects were mediated by the lipoxygenase (LOX) and cytochrome P450 (CYP450) EPA/DHA metabolites, 5-hydroxyeicosapentaenoic acid (HEPE), 4-hydroxydocosahexaenoic acid (HDHA), 18-HEPE, 20-HDHA, 17(18)-epoxyeicosatetraenoic acid (EpETE) and 19(20)-epoxydocosapentaenoic acid (EpDPA), detected here for the first time in human hippocampal neurones using mass spectrometry lipidomics of the supernatant. In fact, like EPA/DHA, co-treatment with these metabolites prevented cytokines-induced reduction in neurogenesis and apoptosis. Moreover, co-treatment with 17(18)-EpETE and 19(20)-EpDPA and the soluble epoxide hydroxylase (sEH) inhibitor, TPPU (which prevents their conversion into dihydroxyeicosatetraenoic acid (DiHETE)/ dihydroxydocosapentaenoic acid (DiHDPA) metabolites) further enhanced their neurogenic and anti-apoptotic effects. Interestingly, these findings were replicated in a sample of n = 22 patients with a DSM-IV Major Depressive Disorder, randomly assigned to treatment with either EPA (3.0 g/day) or DHA (1.4 g/day) for 12 weeks, with exactly the same LOX and CYP450 lipid metabolites increased in the plasma of these patients following treatment with their precursor, EPA or DHA, and some evidence that higher levels of these metabolites were correlated with less severe depressive symptoms. Overall, our study provides the first evidence for the relevance of LOX- and CYP450-derived EPA/DHA bioactive lipid metabolites as neuroprotective molecular targets for human hippocampal neurogenesis and depression, and highlights the importance of sEH inhibitors as potential therapeutic strategy for patients suffering from depressive symptoms.

The omega-3 fatty acid eicosapentaenoic acid (EPA) has multiple actions potentially conferring cardiovascular benefit, including lowering serum triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) levels and potentially reducing key steps in atherogenesis. Dietary supplements are a common source of omega-3 fatty acids in the US, but virtually all contain docosahexaenoic acid (DHA) in addition to EPA, and lipid effects differ between DHA and EPA. Contrary to popular belief, no over-the-counter omega-3 products are available in the US, only prescription products and dietary supplements. Among the US prescription omega-3 products, only one contains EPA exclusively (Vascepa); another closely related prescription omega-3 product also contains highly purified EPA, but is approved only in Japan and is provided in different capsule sizes. These high-purity EPA products do not raise low-density lipoprotein cholesterol (LDL-C) levels, even in patients with TG levels >500 mg/dL, in contrast to the increase in LDL-C levels with prescription omega-3 products that also contain DHA. The Japanese prescription EPA product was shown to significantly reduce major coronary events in hypercholesterolemic patients when added to statin therapy in the Japan EPA Lipid Intervention Study (JELIS). The effects of Vascepa on cardiovascular outcomes are being investigated in statin-treated patients with high TG levels in the Reduction of Cardiovascular Events With EPA-Intervention Trial (REDUCE-IT).

Microalgae offer a promising sustainable source of essential nutrients, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). DHA and EPA are mainly obtained through fish, which are limited in number due to global climate change. Microalgal oil, on the other hand, has emerged as a sustainable and limitless source of DHA and EPA but the bioavailability of these nutrients has not been directly compared to fish oil. Therefore, the objective of this study is to evaluate and demonstrate the comparable DHA and EPA plasma bioavailability of microalgal and fish oil. We analyzed the plasma phospholipid levels of 74 adult men and women after 6 and 14 weeks of consuming omega-3 supplements derived from either microalgal or fish oil in a randomized double-blind placebo-controlled parallel-group clinical trial. We found that the bioavailability of DHA and EPA in plasma phospholipids from microalgal oil supplements are statistically non-inferior compared to fish oil supplements, despite the differences in production process and composition, indicating that microalgal oil is a reliable and bioavailable source of DHA and EPA.

Depressive symptoms may increase the risk of progressing from mild cognitive impairment (MCI) to dementia. Consumption of n-3 PUFA may alleviate both cognitive decline and depression. The aim of the present study was to investigate the benefits of supplementing a diet with n-3 PUFA, DHA and EPA, for depressive symptoms, quality of life (QOL) and cognition in elderly people with MCI. We conducted a 6-month double-blind, randomised controlled trial. A total of fifty people aged >65 years with MCI were allocated to receive a supplement rich in EPA (1·67 g EPA+0·16 g DHA/d; n 17), DHA (1·55 g DHA+0·40 g EPA/d; n 18) or the n-6 PUFA linoleic acid (LA; 2·2 g/d; n 15). Treatment allocation was by minimisation based on age, sex and depressive symptoms (Geriatric Depression Scale, GDS). Physiological and cognitive assessments, questionnaires and fatty acid composition of erythrocytes were obtained at baseline and 6 months (completers: n 40; EPA n 13, DHA n 16, LA n 11). Compared with the LA group, GDS scores improved in the EPA (P = 0·04) and DHA (P = 0·01) groups and verbal fluency (Initial Letter Fluency) in the DHA group (P = 0·04). Improved GDS scores were correlated with increased DHA plus EPA (r 0·39, P = 0·02). Improved self-reported physical health was associated with increased DHA. There were no treatment effects on other cognitive or QOL parameters. Increased intakes of DHA and EPA benefited mental health in older people with MCI. Increasing n-3 PUFA intakes may reduce depressive symptoms and the risk of progressing to dementia. This needs to be investigated in larger, depressed samples with MCI.

Among patients with dry eye disease, those who were randomly assigned to receive oral supplements containing fish-derived n−3 eicosapentaenoic and docosahexaenoic acids did not have significantly better outcomes at 1 year than those who received placebo.

The REDUCE-IT randomized trial demonstrated a cardiovascular benefit of icosapent ethyl (IPE) but also raised potential safety signals for atrial fibrillation (AF) and serious bleeding. We aimed to evaluate the real-world safety of IPE versus mixed omega-3 polyunsaturated fatty acid (OM-3) formulations. This retrospective active comparator new-user cohort study compared rates of new-onset AF and major bleeding (MB) among adult new users of IPE versus OM-3 in 2020-2024 US Veterans Affairs data. Daily drug exposure was determined via prescription dispensing dates. AF and MB outcomes were identified via validated algorithms based on the International Statistical Classification of Diseases and Related Health Problems, 10th revision, clinical modification. Confounding was accounted for via nearest-neighbor pairwise propensity score (PS) matching. The PS, constructed via logistic regression, was informed by expert-identified variables meeting the disjunctive cause criterion. Cox regression was used to estimate adjusted hazard ratios (aHRs), interpretable as average treatment effects for the treated. Cohorts for analyses of AF and MB endpoints included 1927 and 2015 people, respectively, in each of the IPE and OM-3 exposure groups. The median age was 70 years, and the groups exhibited a predominance of white (80%) males (93%). The median follow-up time was 1.29 years per person. Baseline covariates were well balanced by treatment arm after PS matching. Incidence rates for AF were 7.29 versus 7.48 per 100 person-years among new users of IPE versus OM-3. The aHR for AF was 1.15 (95% confidence interval 0.82-1.63). Incidence rates for MB were 3.27 versus 3.35 per 100 person-years among new users of IPE versus OM-3. The aHR for MB was 1.22 (95% confidence interval 0.87-3.02). Our measures of association were consistent with the null, but we were unable to rule out harms from IPE (vs. OM-3) more modest than a 63% increased rate of AF and threefold increased rate of MB.

The systemic bioavailability of free fatty acid (FFA) forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared with ethyl ester (EE) forms is dependent on the presence of intestinal lipases and is highest during consumption of high-fat meals. Given that patients with cardiovascular disease are advised to reduce dietary fat intake, potentially lowering the bioavailability and therapeutic benefit, the hypothesis that FFA forms provide for higher bioavailability compared with EE forms under low-fat diet conditions was tested where the pharmacokinetics of the FFA form (Epanova™) were compared with those of an ethyl ester form (Lovaza®) following repeat dosing. Fifty-two healthy male and female subjects were equally allocated to one of two open-label, parallel-group cohorts. Following a Therapeutic Lifestyle Changes diet for a minimum of 7 days, blood samples were drawn for endogenous values for EPA and DHA over a 24-hour period. Subjects were then administered 4 × 1 g capsules of either Epanova (OM3 FFA) or Lovaza (OM3 EE) once daily for 14 days, following which serial blood samples were drawn over a 24-hour period to characterize the bioavailability of EPA and DHA from the respective formulations. In addition, changes from baseline in lipid profile were explored. Systemic bioavailability, as measured by area under the curve from time zero to 24 hours (AUC(0-τ)) and the maximum measured plasma concentrations during the 0-24 hour dosing interval (C(max,ss)) of unadjusted total plasma EPA + DHA were approximately 3-fold and 3.9-fold higher, respectively, for Epanova relative to Lovaza. Following baseline adjustment, the magnitude of difference in bioavailability was approximately 5.8-fold and 6.5-fold higher in AUC(0-τ) and C(max,ss), respectively, for Epanova relative to Lovaza. Serum triglycerides were reduced by a significantly greater extent (P = 0.013) for Epanova relative to Lovaza (21% versus 8%). The bioavailability of the FFA forms of EPA and DHA in Epanova are significantly greater than the bioavailability from the EE forms present in Lovaza under low-fat dietary conditions normally recommended for patients with cardiovascular disease. This increased bioavailability may lead to improved triglyceride-lowering in patients with hypertriglyceridemia.

Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease. Here, we report the 24-month results of the trial. LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimer's disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705. Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was −0·028 (SD 0·453) in the active group and −0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI −0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of −0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention. The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed. European Commission 7th Framework Programme.

AMR101 is an ω-3 fatty acid agent containing ≥96% pure icosapent-ethyl, the ethyl ester of eicosapentaenoic acid. The efficacy and safety of AMR101 were evaluated in this phase 3, multicenter, placebo-controlled, randomized, double-blinded, 12-week clinical trial (ANCHOR) in high-risk statin-treated patients with residually high triglyceride (TG) levels (≥200 and <500 mg/dl) despite low-density lipoprotein (LDL) cholesterol control (≥40 and <100 mg/dl). Patients (n = 702) on a stable diet were randomized to AMR101 4 or 2 g/day or placebo. The primary end point was median percent change in TG levels from baseline versus placebo at 12 weeks. AMR101 4 and 2 g/day significantly decreased TG levels by 21.5% (p <0.0001) and 10.1% (p = 0.0005), respectively, and non-high-density lipoprotein (non-HDL) cholesterol by 13.6% (p <0.0001) and 5.5% (p = 0.0054), respectively. AMR101 4 g/day produced greater TG and non-HDL cholesterol decreases in patients with higher-efficacy statin regimens and greater TG decreases in patients with higher baseline TG levels. AMR101 4 g/day decreased LDL cholesterol by 6.2% (p = 0.0067) and decreased apolipoprotein B (9.3%), total cholesterol (12.0%), very-low-density lipoprotein cholesterol (24.4%), lipoprotein-associated phospholipase A2 (19.0%), and high-sensitivity C-reactive protein (22.0%) versus placebo (p <0.001 for all comparisons). AMR101 was generally well tolerated, with safety profiles similar to placebo. In conclusion, AMR101 4 g/day significantly decreased median placebo-adjusted TG, non-HDL cholesterol, LDL cholesterol, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, lipoprotein-associated phospholipase A2, and high-sensitivity C-reactive protein in statin-treated patients with residual TG elevations.