Treatment of hypertriglyceridemia with omega-3 fatty acids: a systematic review

PURPOSE: To (a) critically appraise available randomized controlled trials (RCTs) addressing the efficacy of long-chain omega-3 fatty acids as secondary agents for prevention of hypertriglyceridemia and (b) make recommendations for clinical practice. DATA SOURCES: Two independent reviewers examined all RCTs from 1994 to 2003 identified in several databases, extracted data from each study, and used the previously tested Boyack and Lookinland Methodological Quality Index (MQI) to determine study quality. CONCLUSIONS: Ten studies reported long-chain omega-3 fatty acids to be effective in the treatment of hypertriglyceridemia. The average decrease in triglycerides was 29%, total cholesterol 11.6%, very low density lipoprotein (VLDL) 30.2%, and low-density lipoprotein (LDL) 32.5%. One study found LDLs to increase by 25%. The average increase in high-density lipoprotein was 10%. The overall average MQI score was 36% (range = 26% to 54%). Many of the RCTs had serious shortcomings, including short duration, lack of a power analysis, no intention-to-treat analysis, no report of blind assessment of outcome, and lack of dietary control as a confounding variable. IMPLICATIONS FOR PRACTICE: Overall study methodology was weak. Although the evidence supporting use of long-chain omega-3 fatty acids in the secondary prevention of hypertriglyceridemia is reasonably strong, until there are larger RCTs of better methodological quality, it is not recommended that practitioners treat hypertriglyceridemia with omega-3 fatty acid supplementation in lieu of lipid-lowering medications.     

Bariatric surgery reduces fasting total fatty acids and increases n-3 polyunsaturated fatty acids in morbidly obese individuals

Background: Obesity is a global pandemic leading to increased mortality and increased risk of cardiovascular disease. Bariatric surgery is an established treatment of obesity leading to weight loss and reduction of mortality. To further elucidate how bariatric surgery improves metabolic control, we explored the fatty acid (FA) profiles in morbidly obese subjects treated with lifestyle intervention and subsequent bariatric surgery.

Methods: The intervention group consisted of 34 morbidly obese patients scheduled for bariatric surgery and the control group of 17 non-obese patients scheduled for elective laparoscopic procedures. The intervention group had to undergo lifestyle changes preoperatively. Fasting blood samples were drawn at admission, after lifestyle intervention and 1 year after bariatric surgery.

Results: At admission, the morbidly obese patients had significantly higher levels of monounsaturated FAs (MUFAs) and lower levels of n-6 polyunsaturated FAs (PUFAs) and n-3 PUFAs than healthy controls (all p-values <.05). In the intervention group, there was a significantly lower level of total FAs after lifestyle intervention, and from admission to 1 year after surgical intervention (both, p?<?.05), primarily reflecting a lower proportion of saturated FAs (SFAs). Following bariatric surgery, but not after lifestyle changes, there was an increase in the proportion of n-3 PUFA (p?<?.05) reaching levels not significantly different from healthy controls.

Conclusions: Our findings suggest that a reduced proportion of the proposed anti-atherogenic n-3 PUFAs characterizes morbidly obese individuals, and that this FA profile is reversed by bariatric surgery, but not by lifestyle intervention.     

Effects of combination treatment with policosanol and omega-3 fatty acids on platelet aggregation: A randomized, double-blind clinical study

Background:

Policosanol is a mixture of long-chain primary aliphatic alcoholspurified from sugar cane wax that has cholesterol lowering and antiplatelet effects. Omega-3 fatty acids (FA) have triglyceride lowering and antiplatelet effects. Combination treatment with policosanol and omega-3 FA (Ω23FA) has been associated with significant inhibition of platelet aggregation in rabbits compared with either drug alone.

Objective:

The aim of this study was to investigate the effects of combination treatment with Ω3FA (1 g/d) and policosanol (Ω3FA+Poli) compared with Ω3FA (1 g/d) plus placebo (Ω3FA+Pla) on platelet aggregation in human patients with hypercholesterolemia.

Methods:

This randomized, double-blind, clinical study at the Surgical Medical Research Center (Havana City, Cuba) recruited outpatients from lipid clinics, with some atherosclerotic risk factors. Outpatients of both sexes aged 20 to 75 years with serum total cholesterol (TC) levels ≥5 and <6 mmol/L were eligible to enroll. They were included in the study at the end of a 4-week diet stabilization period if their platelet aggregation to arachidonic acid (AA) was ≥50% and serum TC level remained ≥5 mmol/L. Patients were then evenly randomized to receive Ω3FA (1 g/d) + placebo or Ω3FA (1 g/d) + policosanol (10 mg/d) to be taken PO with the evening meal for 21 days. Treatment was assigned according to a randomization code using balanced blocks and a 1:1 allocation ratio. Inhibition of platelet aggregation to AA was the primary efficacy variable, while effects on platelet aggregation to collagen and epinephrine and on lipid profile were secondary variables. Drug compliance and adverse events (AEs) were monitored. Tolerability was assessed using physical examinations and laboratory test results.

Results:

Sixty-four subjects were initially enrolled. Fifty-four patients (30 women, 24 men; mean [SD] age, 58.4 [12] years, [range, 40-70 years]) met the inclusion criteria and were randomized to treatment; 2 groups of 27. After 21 days, platelet aggregation to AA was significantly inhibited in the 2 groups. Ω3FA+Poli inhibited platelet aggregation to all agonists by ≥20%. Platelet aggregation to AA 1.0 and 1.5 mM was inhibited with combination treatment (39.6% and 33.9%, respectively; both P < 0.001 vs baseline; P < 0.001 and P < 0.01, respectively, vs Ω3FA+Pla) and with Ω3FA+Pla (11.0% and 13.3%; both, P < 0.001). Combination treatment was more effective in inhibiting platelet aggregation to AA 1.0 and 1.5 mM in 28.6% (P < 0.001) and 20.6% (P < 0.01), respectively. Platelet aggregation to collagen 1 μg/mL was significantly inhibited with combination treatment and with Ω3FA+Pla compared with baseline (43.2% and 15.1%, respectively; both, P < 0.001), but the effects of combination treatment were significantly greater (P < 0.01). Platelet aggregation to epinephrine 0.1 mM was inhibited with Ω3FA+Poli and Ω3FA+Pla (34.8% and 20.1%; both, P < 0.001), with similar results for both groups. Bleeding time did not change significantly for either group and Ω3FA+Pla did not significantly change the lipid profile. Combination treatment did significantly reduce levels of low-density lipoprotein cholesterol (LDL-C) (17.4%; P < 0.001 vs baseline, P < 0.05 vs Ω3FA+Pla) and TC (10.1%; P < 0.001 vs baseline, P < 0.05 vs Ω3FA+Pla), increase high-density lipoprotein cholesterol (HDL-C) levels (18.0%; P < 0.001 vs baseline), but did not significantly change triglyceride levels. Three patients (2 from the Ω3FA+Poli group and 1 from the Ω3FA+Pla group) withdrew from the trial, though none were due to AEs. Two patients receiving combination treatment reported mild AEs (headache). All treatments were well tolerated.

Conclusions:

In these patients, policosanol (10 mg/d) administered concomitantly with Ω3FA (1 g/d) enhanced the inhibition of platelet aggregation to AA and collagen, but not to epinephrine, compared with Ω3FA+Pla, without significantly affecting bleeding time. Concomitant treatment was also associated with reduced levels of LDL-C and TC and raised HDL-C levels. All treatments were well tolerated.     

Pharmacology and therapeutics of omega-3 polyunsaturated fatty acids in chronic inflammatory disease

Omega-3 (n−3) polyunsaturated fatty acids (n−3 PUFAs) have well documented anti-inflammatory properties, and consequently therapeutic potential in chronic inflammatory diseases. Here we discuss the effects of n−3 PUFAs on various inflammatory pathways and how this leads to alterations in the function of inflammatory cells, most importantly endothelial cells and leukocytes. Strong evidence indicates n−3 PUFAs are beneficial as a dietary supplement in certain diseases such as rheumatoid arthritis; however for other conditions such as asthma, the data are less robust. A clearer understanding of the pharmacology of n−3 PUFAs will help to establish targets to modulate chronic inflammatory diseases.     

Effect of omega-3 fatty acids supplementation on anthropometric indices in children and adolescents: A systematic review and meta-analysis of randomized controlled trials

• •Background Childhood obesity is a major public health problem with a global prevalence greater than 23 %. Omega-3 polyunsaturated fatty acids (omega-3 FAs) supplementation may improve anthropometric indices by increased energy expenditure, attenuated appetite, elevated adiponectin levels, though current evidence is still inconclusive.
• •Objective The aim of this systematic review was to conduct the first comprehensive meta-analysis of randomized controlled trials on the association between omega-3 FAs supplementation and anthropometric indices in children and adolescents.
• •Methods We performed an extensive online database search of the published literature using the SCOPUS, Web of Science, PubMed, EMBASE, and Cochrane library databases from the index date through April 2019. Six studies met inclusion criteria. Changes in anthropometric indices (weight, BMI and waist circumference) were extracted from each article. Statistical heterogeneity was assessed by calculating the I² statistic. We used the standardized mean difference (SMD) with 95 % confidence interval. The meta-analysis was performed based on a random effects model.
• •Results This meta-analysis demonstrated that omega-3 FAs supplementation had no effect on reducing body weight (SMD = -0.00, 95 % CI -0.26 to 0.25), BMI (SMD = -0.07, 95 % CI -0.32 to 0.17) and waist circumference (SMD = -0.16, 95 % CI -0.51 to 0.19).
• •Conclusions Omega-3 FAs supplementation did not change anthropometric indices in children and adolescents. Further large-scale studies with larger sample sizes in children and adolescents are needed to clarify the effects of omega-3 FAs.

     

Prevention of sudden cardiac death with omega-3 fatty acids in patients with coronary heart disease: A meta-analysis of randomized controlled trials

Aim. To systematically review trials concerning the effects of omega-3 fatty acids on sudden cardiac death (SCD), cardiac death, and all-cause mortality in coronary heart disease (CHD) patients.

Methods. PubMed, Embase, and the Cochrane database (1966–2007) were searched. We identified randomized controlled trials that compared dietary or supplementary intake of omega-3 fatty acids with control diet or placebo in CHD patients. Eligible studies had at least 6 months of follow-up data, and cited SCD as an end-point. Two reviewers independently assessed methodological quality. Meta-analysis of relative risk was carried out using the random effect model.

Results. Eight trials were identified, comprising 20,997 patients. In patients with prior myocardial infarction (MI), omega-3 fatty acids reduced relative risk (RR) of SCD (RR = 0.43; 95% CI: 0.20–0.91). In patients with angina, omega-3 fatty acids increased RR of SCD (RR = 1.39; 95% CI: 1.01–1.92). Overall, RR for cardiac death and all-cause mortality were 0.71 (95% CI: 0.50–1.00) and 0.77 (95% CI: 0.58–1.01), respectively.

Conclusions. Dietary supplementation with omega-3 fatty acids reduces the incidence of sudden cardiac death in patients with MI, but may have adverse effects in angina patients.     

The effects of omega-3 polyunsaturated fatty acids on cardiac rhythm: A critical reassessment

Although epidemiological studies provide strong evidence for an inverse relationship between omega-3 polyunsaturated fatty acids (n−3 PUFAs) and cardiac mortality, inconsistent and often conflicting results have been obtained from both animal studies and clinical prevention trials. Despite these heterogeneous results, some general conclusions can be drawn from these studies: 1) n-PUFAs have potent effects on ion channels and calcium regulatory proteins that vary depending on the route of administration. Circulating (acute administration) n−3 PUFAs affect ion channels directly while incorporation (long-term supplementation) of these lipids into cell membranes indirectly alter cardiac electrical activity via alteration of membrane properties. 2) n−3 PUFAs reduce baseline HR and increase HRV via alterations in intrinsic pacemaker rate rather than from changes in cardiac autonomic neural regulation. 3) n−3 PUFAs may be only effective if given before electrophysiological or structural remodeling has begun and have no efficacy against atrial fibrillation. 5) Despite initial encouraging results, more recent clinical prevention and animal studies have not only failed to reduce sudden cardiac death but actually increased mortality in angina patients and increased rather than decreased malignant arrhythmias in animal models of regional ischemia. 6) Given the inconsistent benefits reported in clinical and experimental studies and the potential adverse actions on cardiac rhythm noted during myocardial ischemia, n−3 PUFA must be prescribed with caution and generalized recommendations to increase fish intake or to take n−3 PUFA supplements need to be reconsidered.     

Failure of omega-3 polyunsaturated fatty acids in prevention of migraine: a double-blind study versus placebo

Omega-3 polyunsaturated fatty acids (OPFA) have beneficial effects on inflammatory reactions and production of cytokines. They decrease the release of 5HT by platelets and possess vasorelaxant activity. This led them to be tried in the prophylactic treatment of migraine. After 4 weeks of a single-blind placebo run-in period, patients were randomized and treated in double-blind condition by placebo or OPFA 6 g a day for 16 weeks, followed by a 4-week placebo run-out period. The intention to treat population included 196 patients. Those who received all four treatment periods included 96 patients taking OPFA and 87 taking placebo. The primary efficacy analysis was the number of migraine attacks during the last 4 weeks of treatment. During this period, the mean number of attacks was 1.20 +/- 1.40 in the OPFA group and 1.26 +/- 1.11 in the placebo group (NS). The total number of attacks during the 4-month period of the study was significantly different between groups: 7.05 in the placebo group, 5.95 in the OPFA group (P = 0.036). Mean intensity, mean duration of the attacks and rescue medication use, were not significantly different between the two groups. Except for a significant difference against OPFA for eructations, the tolerance was satisfying. Despite a run-in placebo period of 1 month, a very strong placebo effect was observed in this trial: 45% reduction of the attacks between run-in and 4-month treatment period (55% in the OPFA group, P = 0.058). Finally, this large study did not confirm two previous studies based on a small number of patients.     

Omega-3 polyunsaturated fatty acids and cardiovascular disease: an emphasis on omega-3-acid ethyl esters 90 for the treatment of hypertriglyceridemia

A number of epidemiological/observational studies, as well as large-scale randomized intervention studies, have been conducted to provide evidence for the efficacy of ω-3 fatty acids against atherosclerotic diseases. Currently, ω-3 fatty acids are commercially available in many parts of the world containing the same active ingredients as Lotriga^® (ω-3-acid ethyl esters 90 [O3AE highly concentrated ω-3 fatty acid ethyl esters, consisting of eicosapentaenoic acid-ethyl ester and docosahexaenoic acid-ethyl ester [EPA-E/DHA-E]). A recent head-to-head comparative study of O3AEE90 versus EPA-E demonstrated that O3AEE90 4g/day led to a significantly greater reduction in triglycerides (TG) than EPA-E 1.8g/day and that O3AEE90 2g/day produced comparable effects on TG to those with EPA-E 1.8g/day. While both agents were shown to be useful in lowering TG, the hallmark feature of O3AEE90, that is, the presence of the DHA-E component versus its absence in EPA-E, needs to be further examined for its clinical implications.     

Characterization of NVX-207, a novel betulinic acid-derived anti-cancer compound

Background  Development of betulinic acid derivatives for clinical use has been hampered by adverse pharmacological and physico-chemical characteristics of this class of compounds. We here present a novel semi-synthetic betulinic acid-derived drug candidate well suited for further clinical development.
Materials and methods  In vitro activity and mode of action of NVX-207 were determined using normal as well as cancer cell lines. Gene expression profiling was performed with Affymetrix U133 microarrays. NVX-207 binding partners were identified using a heterobifunctional chemical crosslinker system. Potential binding proteins were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis. Clinical studies were conducted in canine cancer patients suffering from spontaneously arising pre-treated tumours.
Results  NVX-207 showed anti-tumour activity (mean IC₅₀ = 3·5 μM) against various human and canine cell lines. NVX-207-induced apoptosis was associated with activation of the intrinsic apoptotic pathway via cleavage of caspases -9, -3, -7 and of poly (ADP-ribose) polymerase (PARP). Global gene expression profiling demonstrated regulation of genes associated with lipid metabolism, most notably an upregulation of genes coding for insulin-induced gene 1 (Insig-1), low-density lipoprotein receptor (LDL-R) and of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). NVX-207 bound to apolipoprotein A-I, a major regulator of lipid metabolism and cholesterol transport. A phase I/II study in dogs suffering from naturally occurring cancer receiving local treatment of NVX-207 (10 mg mL⁻¹) showed excellent clinical responses including a complete remission in so far 5/5 treated animals.
Conclusions  NVX-207 is well tolerated and has significant anti-cancer activity in vitro and in vivo in dogs with treatment-resistant malignancies.     

ω-3多不饱和脂肪酸对急性呼吸窘迫综合征患者血清炎症介质的影响

目的观察ω-3多不饱和脂肪酸对急性呼吸窘迫综合征（ARDS）患者血清炎症介质释放的影响。方法将42例ARDS患者按随机化数字表原则,分为对照组和研究组,每组各21例。两组患者均接受等氮、等热量的全胃肠外营养,热量25kcal·kg^-1·d^-1、氮摄入量0.2g/kg,其中研究组加用ω-3多不饱和脂肪酸（0.2g·kg^-1·d^-1）,共7d。分别检测治疗前和治疗后第1、3、7天血清白细胞介素1（IL-1）、IL-6、肿瘤坏死因子α（TNF-α）水平,并观察动脉血氧分压和氧合指数的变化。结果加用ω-3多不饱和脂肪酸治疗后,研究组在不同时间点IL-1、IL-6、TNF-α均明显低于对照组（P均〈0.05）;两组患者动脉血氧分压和氧合指数均有改善,且研究组氧合指数较高,差异均有统计学意义（P均〈0.05）。结论ω-3多不饱和脂肪酸可降低ARDS患者IL-1、IL-6、TNF-α水平,在一定程度上有利于ARDS患者呼吸功能的恢复。     

Systems approach to inflammation resolution: identification of novel anti-inflammatory and pro-resolving mediators

Summary.  Using a systems approach to profile self-limited inflammatory exudates, we identified three novel families of lipid-derived mediators, coined the resolvins, protectins and most recently, the maresins that control both the magnitude and duration of inflammation. The mapping of these endogenous resolution circuits provides new avenues to probe the molecular basis of many widely occurring inflammatory diseases. This article focuses on our recent advances on the functional metabolomics of this novel genus of specialized pro-resolving mediators (SPM). SPM include resolvins, protectins and maresins and are biosynthesized from essential omega-3 fatty acid precursors. Each possesses potent multi-pronged actions that proved to be stereoselective with human cells and in animal disease models. Resolvins and protectins are also produced in bone marrow. Together, these findings suggest that defective resolution mechanism(s) may underlie some chronic inflammatory diseases. Moreover, identification of functional SPM biosynthesized during inflammation-resolution indicates that resolution is an active process.     

The limited effect of omega-3 polyunsaturated fatty acids on cardiovascular risk in patients with impaired glucose metabolism: A meta-analysis

Objectives

The impacts of marine-derived n − 3 polyunsaturated fatty acids (n − 3 PUFAs) on cardiovascular risk are not well known. We conducted this meta-analysis to determine the effects of n − 3 PUFAs on cardiovascular outcomes and cardiovascular risk markers in patients with impaired glucose metabolism (IGM).

Design and methods

We searched PUBMED, EMBASE, The Cochrane Library and reference lists of relevant papers for high quality randomized controlled trials comparing dietary intake of n − 3 PUFAs with placebo in IGM patients. Data was extracted and quality assessed independently by two reviewers. Authors were contacted for missing information. Overall estimates were calculated using a random-effects model or a fixed-effects model, and the possibility of publication bias was examined using a funnel plot. Subgroup analyses were conducted to explore the association between the risk markers and study characteristics.

Results

Our meta-analysis included 19 studies, 24,788 patients. Compared with placebo, n − 3 PUFAs had no statistically significant reduce effect on cardiovascular mortality, major cardiovascular events, all-cause mortality or composite endpoint of all-cause mortality or hospitalization for cardiovascular cause, however it can significantly reduce the level of triglycerides (weighted mean difference [WMD] − 0.25 mmol/L; 95% CI − 0.37 to − 0.13: p < 0.001; 12 trials, 13,921 patients).

Conclusion

Marine-derived n − 3 polyunsaturated fatty acids have no protective effect on cardiovascular mortality, major cardiovascular events, all-cause mortality and composite endpoint of all-cause mortality or hospitalization for cardiovascular cause in IGM patients, but can reduce triglyceride level.     

Addition of omega-3 carboxylic acids to statin therapy in patients with persistent hypertriglyceridemia

The incidence of hypertriglyceridemia has grown alongside that of obesity. Statin therapy has been widely recommended for the treatment of dyslipidemias. Omega-3 (OM3) fatty acid concentrates are commonly prescribed concurrently with statins in patients with persistent hypertriglyceridemia for additional lowering of triglyceride and non-HDL cholesterol. The bioavailability of currently available OM3 ethyl ester drugs is limited by their need for hydrolysis by pancreatic lipases, largely stimulated by dietary fat, prior to intestinal absorption. This review will discuss the chemistry, pharmacokinetics and clinical efficacy of a novel OM3 carboxylic acid drug that provides polyunsaturated docosahexaenoic and eicosapentaenoic acids in the free fatty acid form, which is readily absorbed by the intestine. This drug was approved in May 2014 as an adjunct to diet to reduce triglyceride levels in adults with severe (≥500 mg/dl) hypertriglyceridemia.     

ω-3多不饱和脂肪酸对不稳定型心绞痛患者脂蛋白相关性磷脂酶A2的影响

目的探讨ω-3多不饱和脂肪酸对不稳定型心绞痛患者脂蛋白相关性磷脂酶A2的影响。方法选取广东省2家三甲医院60例经皮冠状动脉介入治疗成功的不稳定型心绞痛患者,随机分成对照组和试验组,每组30例。对照组患者术后接受常规的阿司匹林及氯吡格雷治疗,试验组除了接受上述药物治疗外,每日添加服用ω-3 PFUA 1000 mg,记录两组患者一般临床资料,分别在服用ω-3 PFUA前,服用后2周和服用后4周检测患者氧化-LDL和Lp-PLA₂等指标。结果两组患者一般临床资料差异无统计学意义（P>0.05）,两组患者服用ω-3 PFUA前Lp-PLA₂和氧化LDL水平差异无统计学意义（P>0.05）,对照组患者服用ω-3 PFUA 2周及4周后Lp-PLA₂和氧化LDL水平与服用前比较差异无统计学意义（P>0.05）,试验组服用ω-3 PFUA 2周及4周后患者Lp-PLA₂和氧化LDL水平均显著低于服用前及对照组患者（P<0.05）。Lp-PLA₂水平与患者BMI呈正相关（r=0.32,P<0.05）。服用ω-3 PFUA（R²=20.1%,P<0.05）和体质量指数（R²=10.3%,P<0.05）为Lp-PLA₂水平变化的独立预测因素。结论ω-3 PFUA可显著降低不稳定型心绞痛PCI术后患者的Lp-PLA₂水平,这可能是ω-3 PFUA预防心血管疾病发生的潜在机制之一。