Aggiornamento studi Omega 3


1. Br J Nutr. 2019 Jul 2:1-20. doi: 10.1017/S0007114519001582.

Effects of Omega-3-Polyunsaturated Fatty on Endothelial Function in Patients with Peripheral Arterial Disease: A Randomized, Placebo-Controlled, Double-Blind Trial.

Hammer A1, Moertl D2, Schlager O1, Matschuck M3, Seidinger D1, Koppensteiner R1, Steiner S3.



As only limited evidence is available for potential benefits of omega-3 polyunsaturated fatty acids (n3-PUFA) supplementation in patients with peripheral arterial disease (PAD), we studied the effects of 4g n3-PUFA on endothelial function and inflammatory markers. Seventy patients with stable PAD classified as Rutherford stage 2 or 3 and good control of cardiovascular factors were randomized to receive either 4g n3-PUFA or placebo daily for 3 months in a double-blind fashion. Primary endpoint was endothelial function assessed by flow-mediated vasodilation (FMD). In addition, ankle-brachial index (ABI), maximum and pain-free walking distances were determined. Lipid parameters including omega-3 index reflecting n3-PUFA intake as well as pro-inflammatory, endothelial and platelet activation markers were measured over the same time interval. After 3 months of treatment with 4g n3-PUFA daily a significant improvement of FMD was observed compared to placebo (n3-PUFA, median (IQR): Δ 3.7% (-1.8, 7.1) vs. placebo: Δ -0.5% (-6.5, 3.0), P=0.01 between the groups). After a 3 months wash out period this benefit was not sustained (n3-PUFA, median (IQR): Δ 0.6% (-2.2, 5.6) vs. placebo: Δ -0.9% (-6.6, 6,7), P=0.20). In response to n3-PUFA, an improvement of lipid parameters with a pronounced increase of omega-3 index was seen. No changes were found for other parameters. In conclusion, in patients with PAD, 4g/d n3-PUFA improved endothelial function but not walking capacity. Thus, N3-PUFA supplementation might be a potential candidate for reduction of the excess CV risk in PAD patients, which needs testing in large scale trials.


2. Expert Opin Pharmacother. 2019 Jul;20(10):1221-1225. doi: 10.1080/14656566.2019.1609942. Epub 2019 Apr 30.

Clinical trials of eicosapentaenoic acid (EPA) prescription products for the treatment of hypertriglyceridemia.

Doggrell SA1.


Introduction: Hypertriglyceridemia is common and increases cardiovascular risk. Fish oil decreases triglyceride levels, but also increases low-density lipoprotein (LDL) cholesterol, which may negate any cardiovascular benefits. EPA, a component of fish oil, reduces triglyceride levels without increasing LDL cholesterol. Areas covered: Two forms of purified EPA ethyl ester are available on prescription. This review considers the clinical trials of these purified esters to treat hypertriglyceridemia and shows that the EPA ethyl esters reduce triglyceride levels and reduce cardiovascular events. Expert opinion: To date, the effects of the purified EPA ethyl esters on cardiovascular events have only been tested in subjects taking statins. With statin treatment, if hypertriglyceridemia persists, it may be worthwhile considering adding an EPA ethyl ester. However, as the fibrates reduce the triglyceride levels by similar amounts to the EPA ethyl esters, while increasing the levels of HDL cholesterol, they are an alternative to EPA ethyl esters in combination with statins. As the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors reduce triglycerides to a similar extent to the EPA ethyl ester, while reducing LDL cholesterol levels to a greater extent than the statins, they should be considered as an alternative to the statin/EPA ethyl ester combination.


3. Proc Nutr Soc. 2019 Mar 6:1-6. doi: 10.1017/S0029665118002902. [Epub ahead of print]

n-3 Fatty acids and risk for fatal coronary disease.

Harris WS1, Zotor FB2.


The purpose of this review is to consider the effects of the long-chain n-3 fatty acids found in marine foods, EPA and DHA, on risk for CVD, particularly fatal outcomes. It will examine both epidemiological and randomised controlled trial findings. The former studies usually examine associations between the dietary intake or the blood levels of EPA + DHA and CVD outcomes or, on occasion, total mortality. For example, our studies in the Framingham Heart Study and in the Women's Health Initiative Memory Study have demonstrated significant inverse relations between erythrocyte EPA + DHA levels (i.e. the Omega-3 Index) and total mortality. Recent data from the Cardiovascular Health Study reported the same relations between plasma phospholipid n-3 levels and overall healthy ageing. As regards randomised trials, studies in the 1990s and early 2000s were generally supportive of a cardiovascular benefit for fish oils (which contain EPA + DHA), but later trials were generally not able to duplicate these findings, at least for total CVD events. However, when restricted to effects on risk for fatal events, meta-analyses have shown consistent benefits for n-3 treatment. Taken together, the evidence is strong for a cardioprotective effect of EPA + DHA, especially when consumed in sufficient amounts to raise blood levels into healthy ranges. Establishing target EPA + DHA intakes to reduce risk for cardiovascular death is a high priority.



1. Medicine (Baltimore). 2018 Dec;97(50):e13593. doi: 10.1097/MD.0000000000013593.

Comparison of efficacy and safety of combination therapy with statins and omega-3 fatty acids versus statin monotherapy in patients with dyslipidemia: A systematic review and meta-analysis.

Choi HD, Chae SM.



Dyslipidemia is a major risk factor for the development of cardiovascular disease. Both statins and omega-3 fatty acids demonstrate beneficial effects on lipid concentrations. The goal was to evaluate the safety and efficacy of combination therapy with statins and omega-3 fatty acids.


We performed a systematic review and meta-analysis of published data to compare the safety and efficacy of combination therapy with statins and omega-3 fatty acids versus statin monotherapy in patients with dyslipidemia. Six articles were assessed in the present meta-analysis (quantitative assessment) and qualitative assessment.


In terms of efficacy, the combination treatment afforded a significantly greater reduction in total cholesterol/high-density lipoprotein cholesterol than statin alone did [standard difference in means = -0.215; 95% confidence interval (CI) -0.359--0.071]. However, there was no significant difference in low-density lipoprotein (LDL) cholesterol between the 2 groups. Qualitative assessment of other lipid parameters was performed. Combination therapy with statins and omega-3 fatty acids was generally more effective on lipid concentration than statin monotherapy. In terms of safety, there were no significant differences in total adverse events between the 2 groups. Gastrointestinal adverse events were found to be significantly increased in patients receiving combination therapy using the fixed-effects model (relative risk = 0.547; 95% CI 0.368-0.812).


We suggest that combination therapy with statins and omega-3 fatty acids enhances lipid profile, except LDL cholesterol, compared with statin monotherapy. Nevertheless, statin and omega-3 fatty acid combination should be cautiously recommended, taking into account the clinical importance of LDL cholesterol and safety issues associated with their concomitant use




1. J Nutr Biochem. 2019 Feb;64:45-49. doi: 10.1016/j.jnutbio.2018.09.027. Epub 2018 Oct 11.

Omega-3 polyunsaturated fatty acids attenuate inflammatory activation and alter differentiation in human adipocytes.

Ferguson JF1, Roberts-Lee K2, Borcea C1, Smith HM1, Midgette Y2, Shah R3.



mega-3 polyunsaturated fatty acids, specifically the fish-oil-derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been proposed as inflammation-resolving agents via their effects on adipose tissue.


We proposed to determine the effects of EPA and DHA on human adipocyte differentiation and inflammatory activation in vitro.


Primary human subcutaneous adipocytes from lean and obese subjects were treated with 100 μM EPA and/or DHA throughout differentiation (differentiation studies) or for 72 h postdifferentiation (inflammatory studies). THP-1 monocytes were added to adipocyte wells for co-culture experiments. Subcutaneous and visceral adipose explants from obese subjects were treated for 72 h with EPA and DHA. Oil Red O staining was performed on live cells. Cells were collected for mRNA analysis by quantitative polymerase chain reaction, and media were collected for protein quantification by enzyme-linked immunosorbent assay.


Incubation with EPA and/or DHA attenuated inflammatory response to lipopolysaccharide (LPS) and monocyte co-culture with reduction in post-LPS mRNA expression and protein levels of IL6, CCL2 and CX3CL1. Expression of inflammatory genes was also reduced in the endogenous inflammatory response in obese adipose. Both DHA and EPA reduced lipid droplet formation and lipogenic gene expression without alteration in expression of adipogenic genes or adiponectin secretion.


EPA and DHA attenuate inflammatory activation of in vitro human adipocytes and reduce lipogenesis.


2. Nutrients. 2019 Feb 20;11(2). pii: E438. doi: 10.3390/nu11020438.

Diet Supplementation in ω3 Polyunsaturated Fatty Acid Favors an Anti-Inflammatory Basal Environment in Mouse Adipose Tissue.

Colson C1, Ghandour RA2, Dufies O3, Rekima S4, Loubat A5, Munro P6, Boyer L7, Pisani DF8,9.



Oxylipins are metabolized from dietary ω3 and ω6 polyunsaturated fatty acids and are involved in an inflammatory response. Adipose tissue inflammatory background is a key factor of metabolic disorders and it is accepted that dietary fatty acids, in terms of quality and quantity, modulate oxylipin synthesis in this tissue. Moreover, it has been reported that diet supplementation in ω3 polyunsaturated fatty acids resolves some inflammatory situations. Thus, it is crucial to assess the influence of dietary polyunsaturated fatty acids on oxylipin synthesis and their impact on adipose tissue inflammation. To this end, mice fed an ω6- or ω3-enriched standard diet (ω6/ω3 ratio of 30 and 3.75, respectively) were analyzed for inflammatory phenotype and adipose tissue oxylipin content. Diet enrichment with an ω3 polyunsaturated fatty acid induced an increase in the oxylipins derived from ω6 linoleic acid, ω3 eicosapentaenoic, and ω3 docosahexaenoic acids in brown and white adipose tissues. Among these, the level of pro-resolving mediator intermediates, as well as anti-inflammatory metabolites, were augmented. Concomitantly, expressions of M2 macrophage markers were increased without affecting inflammatory cytokine contents. In vitro, these metabolites did not activate macrophages but participated in macrophage polarization by inflammatory stimuli. In conclusion, we demonstrated that an ω3-enriched diet, in non-obesogenic non-inflammatory conditions, induced synthesis of oxylipins which were involved in an anti-inflammatory response as well as enhancement of the M2 macrophage molecular signature, without affecting inflammatory cytokine secretion.




1. Connect Tissue Res. 2018 Jul;59(4):316-331. doi: 10.1080/03008207.2017.1385605. Epub 2017 Oct 17.

Leptin alone and in combination with interleukin-1-beta induced cartilage degradation potentially inhibited by EPA and DHA.

Phitak T1, Boonmaleerat K1, Pothacharoen P1, Pruksakorn D2, Kongtawelert P1.


Osteoarthritis (OA) is the most common form of arthritis. Obesity has been believed to be an important risk factor for OA development and the progression of not only load-bearing joints, but low-load-bearing joints as well. Increased leptin has been the focus of a link between obesity and OA. In this study, the effects of pathological (100ng/ml) or supra-pathological (10μg/ml) concentrations of leptin alone or in combination with IL1β on cartilage metabolisms were studied in porcine cartilage explant. The involved mechanisms were examined in human articular chondrocytes (HACs). Moreover, the protective effect of omega-3 polyunsaturated acids, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) was also investigated. Leptin (10μg/ml) alone or in combination with IL1β could induce cartilage destruction, although lower concentrations had no effect. Leptin activated NFκB, ERK, JNK and p38 in HACs, which led to the induction of MMP3, MMP13 and ADAMTS4 secretions. The combined effect could further induce those enzymes through the additive effect on activation of NFκB and JNK. Interestingly, both EPA and DHA could inhibit cartilage damage induced by leptin plus IL1β by reducing the activation of NFκB and JNK, which led to the decrease of ADAMTS4 secretion. Altogether, only a supra-pathological concentration of leptin alone or in combination with IL1β could induce cartilage destruction, whereas a pathological one could not. This effect could be inhibited by EPA and DHA. To gain greater understanding of the link between leptin and OA, the effect of different levels of leptin on several states of OA cartilage requires further investigation.


2. J Altern Complement Med. 2011 Nov;17(11):1051-63. doi: 10.1089/acm.2010.0410.


A randomized, double-blinded, placebo-controlled study of the effect of a combination of lemon verbena extract and fish oil omega-3 fatty acid on joint management.


Caturla N1, Funes L, Pérez-Fons L, Micol V.




The aim of this study was to test the efficacy of an antioxidant/anti-inflammatory supplement containing standardized lemon verbena (Aloysia triphylla, Lippia citriodora) extract and fish oil omega-3 fatty acid in a human pilot trial as an alternative treatment for joint management.


First, antioxidant activity of the supplement was determined through an oxygen radical absorbance capacity (ORAC) assay. In a randomized, double-blinded placebo-controlled trial, 45 subjects with pain discomfort received the nutritional supplement or placebo for 9 weeks. Western Ontario MacMaster (WOMAC) and Lequesne's questionnaires, which are disease-specific measurements validated to measure joint dysfunction and pain, were administered and evaluated once per week in the placebo and intervention groups.


Pain and stiffness symptoms, and joint function were determined once per week through recording their respective WOMAC and Lequesne's scores in the placebo and intervention groups. Statistically significant differences were determined at every measurement point between the two groups.


Lemon verbena extract showed strong antioxidant properties as measured by the ORAC assay. The nutritional supplement containing standardized lemon verbena extract (14% verbascoside, w/w) and fish oil omega-3 fatty acid reduced symptoms of pain and stiffness significantly, and improved physical function as shown by WOMAC and Lequesne's scores after 9 weeks of treatment. WOMAC and Lequesne's total scores decreased 53% and 78%, respectively, at the end of the study compared to initial conditions. Onset of the effect was observed at the third and fourth weeks, when statistically significant differences were detected, compared to placebo.


This pilot study reveals that supplementation with lemon verbena combined with omega-3 fatty acids may be considered for further investigation as a complementary and alternative treatment for improving joint status in subjects with joint discomfort.





1. Curr Neuropharmacol. 2018 Mar; 16(3): 308–326.

The role of Physical Exercise and Omega-3 Fatty Acids in Depressive Illness in the Elderly

Stefano Farioli-Vecchioli,1 Stefano Sacchetti,2,3 Nicolis V. di Robilant,1 and Debora Cutuli2,3,*



In adulthood, depression is the most common type of mental illness and will be the second leading cause of disease by 2020. Major depression dramatically affects the function of the central nervous system and degrades the quality of life, especially in old age.

Several mechanisms underlie the pathophysiology of depressive illness, since it has a multifactorial etiology. Human and animal studies have demonstrated that depression is mainly associated with imbalances in neurotransmitters and neurotrophins, hypothalamic-pituitary-adrenal axis alterations, brain volume changes, neurogenesis dysfunction, and dysregulation of inflammatory pathways. Also the gut microbiota may influence mental health outcomes.

Although depression is not a consequence of normal aging, depressive disorders are common in later life, even if often undiagnosed or mis-diagnosed in old age. When untreated, depression reduces life expectancy, worsens medical illnesses, enhances health care costs and is the primary cause of suicide among older people. To date, the underpinnings of depression in the elderly are still to be understood, and the pharmacological treatment is the most commonly used therapy.


Since a sedentary lifestyle and poor eating habits have recently emerged as crucial contributors to the genesis and course of depression, in the present review, we have focused on the effects of physical activity and omega-3 fatty acids on depressive illness in the elderly.


A growing literature indicates that both exercise and dietary interventions can promote mental health throughout one’s lifespan.


There thus emerges the awareness that an active lifestyle and a balanced diet may constitute valid low-cost prevention strategies to counteract depressive illness in the elderly.




​​​​​​​1. J Ophthalmol. 2018 Sep 17;2018:8259371. doi: 10.1155/2018/8259371. eCollection 2018.

Effects of Oral Supplementation with Docosahexaenoic Acid (DHA) plus Antioxidants in Pseudoexfoliative Glaucoma: A 6-Month Open-Label Randomized Trial.

Romeo Villadóniga S1, Rodríguez García E1, Sagastagoia Epelde O2, Álvarez Díaz MD1, Domingo Pedrol JC3.




To assess the effects of antioxidant oral supplementation based on docosahexaenoic acid (DHA) in pseudoexfoliative (PEX) glaucoma.

Patients and Methods:

A prospective 6-month open-label randomized controlled trial was conducted in patients with PEX glaucoma and adequate intraocular pressure (IOP) control. Patients in the DHA group received a high-rich DHA (1 g) nutraceutical formulation. Ophthalmological examination, DHA erythrocyte membrane content (% total fatty acids), plasma total antioxidant capacity (TAC), plasma malondialdehyde (MDA), and plasma IL-6 levels were assessed.


Forty-seven patients (DHA group 23, controls 24; mean age 70.3 years) were included. In the DHA group, the mean IOP in the right eye decreased from 14.7 [3.3] mmHg at baseline to 12.1 [1.5] mmHg at 6 months (P=0.01). In the left eye, IOP decreased from 15.1 [3.3] mmHg at baseline to 12.2 [2.4] mmHg at 6 months (P=0.007). DHA erythrocyte content increased in the DHA group, with significant differences versus controls at 3 months and 6 months (8.1% [0.9] vs. 4.4% [0.7]; P < 0.0001). At 6 months and in the DHA group only, TAC levels as compared with baseline increased significantly (919.7 [117.9] vs. 856.9 [180.3] µM copper-reducing equivalents; P=0.01), and both MDA (4.4 [0.8] vs. 5.2 [1.1] nmol/mL; P  =  0.02) and IL-6 (2.8 [1.3] vs. 4.7 [2.3] pg/mL; P=0.006) levels were lower than in controls.


Targeting pathophysiology mechanisms of PEX glaucoma by reducing oxidative stress and inflammation with a high-rich DHA supplement might be an attractive therapeutic approach. Despite the short duration of treatment, decrease in IOP supports the clinical significance of DHA supplementation.