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Effects of n-3 PUFA on Major Chronic Diseases: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by David Ma.

There has been heightened interest in the health benefits of n-3 polyunsaturated fatty acids (PUFA) in reducing chronic diseases such as, cardiovascular disease (CVD), cancer, type 2 diabetes, and acute macular degeneration (AMD).

  • cardiovascular disease (CVD)
  • n-3 polyunsaturated fatty acid(n-3 PUFA)
  • cancer

1. Introduction

N-3 long chain polyunsaturated fatty acids (n-3 PUFA) have an important role in human health and reduction in chronic diseases [1]. N-3 PUFA are presumed to have anti-inflammatory and anti-thrombotic properties, lower plasma triglycerides and low-density lipoprotein (LDL) cholesterol, improve vasomotor and endothelial functions, and inhibit cell growth factors [2,3][2][3]. There are three main types of n-3 PUFA, and they are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). EPA and DHA most specifically are vital for improved cardiovascular functions, neurodevelopment, and in improving metabolic and immune processes [1]. However, it is challenging to obtain enough EPA and DHA solely from diet as they cannot be synthesized by the body and must therefore be supplemented through fish and fish oil supplements [4]. Since EPA and DHA are important for human health, numerous health organizations have recommended 250–500 mg of EPA and DHA per day [1]. While the importance of EPA and DHA for human health is recognized, there are still no established dietary reference intakes (DRIs) for EPA and DHA, though some researchers have been calling for it as this may help “inform nutrition policy decisions and reduce consumer uncertainty” [5].
Over the years, due to industrialization, there has been a reduction in the intake of n-3 PUFA, and increased consumption of highly processed foods rich in saturated fats and n-6 PUFA [6]. Consequently, a diet low in n-3 PUFA and high in saturated fats and n-6 PUFA is associated with poorer metabolic and cardiovascular health in both men and women [6]. Because of heightened interest in the health benefits of n-3 PUFA, there has been an increased intake of fish oil supplements among the general public, and a plethora of research on the potential effects of n-3 PUFA in reducing incidence of chronic and age-related diseases such as cardiovascular disease (CVD), cancer, type 2 diabetes, and acute macular degeneration (AMD) [7]. However, findings from randomized controlled trials (RCTs) studying the effects of n-3 PUFA supplementation on chronic disease prevention have been inconclusive, generally showing a beneficial or neutral, but not negative outcome. Additionally, the conflicting emerging evidence from newly published systematic reviews and meta-analyses (SRMA) of RCTs on the effects of n-3 PUFA on total CVD and its related outcomes, cancer incidence and cancer mortality has raised concerns about the role of n-3 PUFA in reducing and preventing chronic diseases due to challenges inherent to human studies in nutrition [8,9,10,11,12][8][9][10][11][12].

2. Effects of n-3 PUFA on Major Chronic Diseases

2.1. Cardiovascular Disease

Previous observational studies reported that consumption of fish once or twice per week was associated with lower risks of fatal coronary heart disease (CHD), but cohort studies are subject to confounding factors and biases and are unable to establish causality [13,14,15][13][14][15]. Hence, there has been an increasing interest among the scientific community to assess whether n-3 PUFA has a protective effect on CVD risk and its related outcomes such as myocardial infarction (MI), stroke, CHD and CVD mortality. Several trials studying the cause-and-effect relationship between n-3 PUFA intake and its effects on CVD and its outcomes have subsequently reported “discordant trial results” [8]. Recent evidence from SRMAs demonstrated a significant reduction in incidence of MI, CHD, total CVD, and CVD mortality after supplementation with n-3 PUFA [9,11,16,17][9][11][16][17]. Additionally, a dose–response meta-analysis showed that a dose of 10 g/day × years increments of n-3 PUFA for a longer duration was associated with a 13% reduction in major cardiovascular events [9]. Large-scale trials, with doses of n-3 PUFA (EPA, DHA, or EPA + DHA) ranging from 0.85 to 4 g daily and with a follow-up ranging from 3.5 to 4.9 years reported significant reductions in CVD, CHD, MI, stroke, and their related fatalities [18,19,20,21][18][19][20][21] (Table 1). The Gruppo Italiano perlo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) Prevenzione trial, an open-label RCT involving 11,324 participants with recent MI reported a 20% reduction in the primary composite of death, non-fatal MI and non-fatal stroke in the group receiving 1 g of EPA + DHA daily for 3.5 years [21]. Another open-label RCT, the GISSI-Heart Failure (HF) trial with 7046 patients with evidence of heart failure significantly reduced CVD mortality by 8% after a supplementation of 0.85–0.88 g of EPA + DHA every day for almost 4 years [19]. The Japan EPA Lipid Intervention Study (JELIS), an open-label trial conducted among 18,645 hypercholesterolemic patients further reduced major coronary events by 19% after a supplementation of 1.8 g of EPA and 5–10 mg of statin daily for 4.6 years [18]. A recent randomized, double-blind, placebo-controlled trial, the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), reported a 25% reduction in the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina after a daily intake of 4 g of EPA daily for a median follow-up of 4.9 years [20]. In contrast, eleven large-scale trials with doses of n-3 PUFA ranging from 0.84 to 4 g daily and with a follow-up of 1 to 7.4 years reported no significant association with CVD and its sub types [22,23,24,25,26,27,28,29,30,31,32][22][23][24][25][26][27][28][29][30][31][32] (Table 1). Two of these large-scale trials, The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) [25] and a Study of Cardiovascular Events in Diabetes (ASCEND) [29] studied the effects of n-3 PUFA on cardiovascular outcomes in patients with impaired fasting glucose or with diabetes, but without evidence of atherosclerotic CVD. Both had more than 12,000 participants enrolled, taking 0.84 g of DHA + EPA for more than 6 years, and still failed to show any significant reduction in CVD and its related outcomes [25,29][25][29]. Moreover, the Vitamin D and Omega-3 Trial (VITAL), a study of 25,871 subjects with no previous CVD risk factors taking 0.84 g EPA + DHA with 2000 IU of vitamin D daily for more than 5 years also reported no significant reduction in major cardiovascular events or mortality [30]. Likewise, two other large-scale trials, namely the Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia (STRENGTH) and the Omega-3 fatty acids in Elderly with Myocardial Infarction (OMEMI) demonstrated null findings after combined EPA + DHA therapy [31,32][31][32]. The STRENGTH trial was even stopped early because of a low possibility of demonstrating any clinical benefits [31].
Table 1.
Characteristics of RCTs examining the effects of
n
-3 PUFA on CVD and CVD-related outcomes.
Author, Publication Country Follow-Up Sample Size; (Test/Control), Description Number of Women, % Age (Range, Mean) Doses of n-3PUFA vs. Placebo Outcomes (Test/Control) Results
Marchioli 2002—GISSI-P [21] Italy 3.5 years 11,324; (5666/5658), pts with recent MI 1665

(14.7%)		 59.3 years 1 g EPA + DHA + 300 mg Vit E/d or placebo Total CVD 556/621; MI 223/233; CVD mortality 310/370; CHD mortality 209/258; Stroke 92/77 Significant reduction in Total CVD, RR 0.80 (95% CI 0.68–0.94), p < 0.01; CVD mortality, RR 0.70 (95% CI 0.56–0.86), p < 0.001; CHD mortality, RR 0.68 (95% CI 0.53–0.88), p < 0.01
Yokoyama 2007—JELIS [18] Japan 4.6 years 18,645; (9326/9319) hypercholesterolemic patients on statin 12,786

(68.6%)		 61 years 1.8 g EPA + 5–10 mg statin/d or placebo (5–10 mg statin) Total CHD (Major Coronary events) 262/324; MI 73/97; Stroke 166/162; CHD mortality 29/31; MI mortality 11/14 Significant reduction in Total CHD, HR 0.81 (95% CI 0.69–0.95), p = 0.011
Tavazzi 2008—GISSI-HF [19] Italy 3.9 years 7046; (3529/3517), pts with clinical evidence of heart failure 1516 (20.5%) 67 years 0.85–0.882 g EPA + DHA or placebo (olive oil) CVD mortality 712/765; MI 107/129; Stroke 122/103; MI mortality 307/325; Stroke mortality 50/44 Significant reduction in CVD mortality, HR 0.92 (95% CI 0.83–1.02), p = 0.045
Galan 2010—

SU.FOL.OM3 [22]		 France 4.7 years 2501; (1253/1248), pts with a history of acute coronary or ischemic event 1 year before randomization 509

(20.4%)		 60.6 years 0.9 g EPA + DHA + 560 μg Folate + 3 mg vitamin B-6 + B-12 (20 μg) or placebo Total CVD 81/76; MI 32/28; CHD 51/53; Stroke 40/43 No effect on Total CVD, HR 1.08 (95% CI 0.79–1.47)
Rauch 2010—

OMEGA [23]		 Germany 1 year 3818; (1925/1893), pts with MI 977

(25.6%)		 64 years 1 g EPA + DHA/d or placebo (olive oil) Total CVD 182/149;

MI mortality 28/29		 No effect on Total CVD, OR 1.21 (95% CI 0.96–1.52)
Kroumhout et al., 2010—Alpha Omega Trial [24] The Netherlands 3.3 years 4837; (2404/2433), pts with MI and receiving antihypertensive, antithrombotic, and lipid-modifying therapy 1054 (21.8%) 69.1 years 2 g ALA + 0.4 g EPA + DHA/d or placebo CVD 170/185; CVD mortality 80/82; CHD mortality 67/71 No effect on Total CVD, HR 0.92 (95% CI 0.75–1.13) and other CVD outcomes
Bosch 2012—ORIGIN Trial [25] 573 centers in 40 countries globally 6.2 years 12,537; (6281/6255) pts with impaired fasting glucose, impaired glucose tolerance or diabetes 4386

(35%)		 63.5 years 0.84 g EPA + DHA or placebo (olive oil). Total CVD 1034/1017; CVD mortality 574/581; MI 344/316; Stroke 314/336 No effect on Total CVD, HR 1.01 (95% CI 0.93–1.10), and other CVD outcomes
Roncaglioni 2013—Risk & Prevention Study [26] Italy 5 years 12,513; (6244/6269), pts with multiple CVD risk factors 4818

(38.5%)		 64 years 1 g EPA + DHA/d or placebo (olive oil) Total CVD 733/745; CVD mortality 142/137; MI 310/324; MI mortality; 82/76 No effect on Total CVD, HR 0.98 (95% CI 0.88–1.08) and other CVD outcomes
Bonds 2014—

AREDS2 [27]		 USA 4.8 years 4203; (2056/2147), pts with retinal findings consistent with advanced age-related macular degeneration 2387

(56.8%)		 74.3 years 1 g EPA + DHA or placebo ± 10 mg lutein + 2 mg zeaxanthin Total CVD 183/187 No effect on Total CVD, HR 0.95 (95% CI 0.78–1.17)
Andrieu et al., 2017—

MAPT [28]		 France and Monaco 3 years 1525; (755/770), community–dwelling and non demented pts over 70 978

(64%)		 75.3 years 1.025 g EPA + DHA/d or placebo (paraffin oil) Total CVD (cardiac and vascular disorders) 192/164; Stroke 1/2 No effect on Total CVD and stroke
Bowman 2018—

ASCEND [29]		 UK 7.4 years 15,480; (7740/7740), pts with diabetes but without evidence of atherosclerotic cardiovascular disease 5796

(37.4%)		 63.3 years 0.84 g EPA + DHA or placebo (olive oil) CVD 689/712; MI 186/200; Stroke 217/214; CVD mortality 196/240; CHD mortality 100/127; Stroke mortality 35/37 No effect on Total CVD, RR 0.97 (95% 0.87–1.08) and other CVD outcomes
Bhatt 2019—REDUCE IT Trial [20] Australia, Canada, New Zealand, South Africa, the Netherlands, and USA 4.9 years 8179; (4089/4090), pts with CVD or with diabetes and other risk factors, receiving statin therapy 2357

(28.8%)		 64 years 4 g EPA/d or placebo (mineral oil) Total CVD 705/901; MI 355/250; CVD mortality 174/213; Stroke 98/134 Significant reduction in Total CVD, HR 0.75 (0.95% CI 0.68–0.83), p < 0.001; MI, HR 0.69 (95% CI 0.58–0.81), p < 0.001; CVD mortality, HR 0.80 (95% CI 0.66–0.98), p = 0.03; Stroke, HR 0.72 (95% CI 0.55–0.93), p = 0.01
Manson 2019—

VITAL [30]		 USA 5.3 years 25,871; (12,933/12,938), healthy men and women (no previous history of CVD, MI, stroke) 13,085

(50.6%)		 67.1 years 0.84 g EPA + DHA+ 2000 IU Vit Ds/d or placebo (corn oil) Total CVD 386/419; Total CHD 308/370; MI 145/200; Stroke 148/142; CVD mortality 142/148; CHD mortality 37/49; MI mortality 13/26; Stroke mortality 22/30 No effect on Total CVD, HR 0.92 (95% CI 0.80–1.06) and other CVD outcomes
Nicholls 2020—

STRENGTH [31]		 Asia, Australia, Europe, New Zealand, North America, South Africa, South America 5 years 13,078; (6539/6539), statin-treated participants with high CVD risk, hypertriglyceridemia, and low levels of HDL-C. 4568

(34.9%)		 62.5 years 4 g EPA + DHA/d or placebo (corn oil) Total CVD 785/795; MI 218/226; Stroke 142/125; CVD mortality 228/211 No effect on Total CVD, HR 0.99 (95% CI 0.90–1.09) and other CVD outcomes
Kalstad 2020—

OMEMI [32]		 Norway 2 years 1027; (513/154), pts with recent acute myocardial infarction 294

(28.6%)		 75 years 1.6 g EPA + DHA or placebo (corn oil) Total CVD 108/102; MI 39/35; Stroke 17/12 No effect on Total CVD, HR 1.07 (95% CI 0.82–1.40) and other CVD outcomes
AREDS 2, Age-Related Eye Disease Study 2; ASCEND, A Study of Cardiovascular Events in Diabetes; CI, confidence interval; CVD, cardiovascular disease; CHD, coronary heart disease; d, day; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GISSI-P, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Prevenzione; GISSI-HF, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Heart Failure; HR, hazard ratio; HDL-C, high density lipoprotein cholesterol; IU, International Unit; JELIS, Japan EPA Lipid Intervention Study; MAPT, Multidomain, Alzheimer Preventive Trial; MI, myocardial infarction; pts, patients; PUFA, polyunsaturated fatty acids; OR, odds ratio; OMEMI, Omega-3 fatty acids in Elderly with Myocardial Infarction; ORIGIN, Outcome Reduction With Initial Glargine Intervention; RR, relative risk; REDUCE-IT, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial; STRENGTH, Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia; SU.FOL.OM3, Supplémentation en Folates et Omega-3; VITAL, VITamin D and OmegA-3 TriaL.

2.2. Cancer

In 2020 alone, cancer was the leading cause of morbidity and death globally with approximately 19.3 million new cancer cases and 10 million cancer-related deaths [33]. Since cancer incidence and mortality are on the rise, it has been suggested that the intake of n-3 PUFA may reduce cancer risk by regulating metabolic pathways and inflammatory responses, oxidative stress, and changes in the composition of membrane affecting cell signaling pathways [34,35][34][35]. It was demonstrated in vitro and in animal studies that n-3 PUFA may inhibit breast cancer growth [36]. Asian countries with the highest intake of n-3 PUFA had a significantly lower rate of breast cancer compared to Europe and United States [37]. A greater incidence of breast cancer was further observed among Asian–American women migrating to the West due to a shift from their traditional fish-based diet to a high-fat Western diet [38]. Earlier evidence focusing on Asian populations showed a protective benefit of n-3 PUFA, with a 20% and 26% reduction in breast cancer risk in both Japanese and Singaporean Chinese populations, respectively [39,40][39][40]. A more recent dose–response meta-analysis demonstrated a 6% decrease in breast cancer risk for every 1% increase in circulating n-3 PUFA [41]. However, the evidence of n-3 PUFA on cancer development and cancer mortality risk remains contradictory when considering all cancer types. Epidemiological studies demonstrating significant reductions in cancer risk may have overestimated the effects of n-3 PUFA supplementation, leading us to believe that estimates of cancer risk need to be assessed by cancer type and it is not possible to generalize across all cancers. An earlier SRMA of observational studies showed significant associations between n-3 PUFA and cancer incidence, especially colorectal, lung, prostate, and breast cancer [42]. More than three decades ago, the Lyon Diet Heart Study, a trial consisting of 605 MI survivors, reported that supplementing the Mediterranean diet with a margarine rich in n-3 PUFA reduced cancer risk by 61% after a 4 year follow up [43]. In contrast, a current SRMA of RCTs extensively examining the high-quality evidence of the effects of n-3 PUFA on cancer demonstrated little or no effect on cancer diagnosis and cancer mortality [12]. Consequently, the same study reported a slight increase in prostate cancer risk after an intake of ALA, although the certainty of evidence was of low-quality [12]. Most recently, large-scale RCTs such as GISSI-P, JELIS, ORIGIN, ASCEND, and VITAL showed null effects on cancer incidence and cancer mortality after more than 3.5 years of follow-up and with doses of EPA + DHA combined ranging from 0.84–1.8 g [18,29,30,44,45,46][18][29][30][44][45][46]. Some small scale RCTs also examining the effects of n-3 PUFA on cancer incidence and mortality for a mean follow-up of 1.5 years found no association with cancer outcomes [47,48,49][47][48][49].

2.3. Type 2 Diabetes

With more than 700 million people projected to be diagnosed with type 2 diabetes by 2045, there is a need to prevent and manage this endocrine disease because of its association with increased risks of CVD and cancer [50]. Type 2 diabetes is also associated with a variety of modifiable risk factors that can be prevented by following a healthy diet and lifestyle [51]. Thus, people are now turning to n-3 PUFA supplementation to manage the symptoms associated with type 2 diabetes such as elevated blood glucose and insulin resistance [52]. Over the years, animal and cell culture studies have shown that n-3 PUFA may prevent type 2 diabetes through anti-inflammatory properties, insulin signaling, changing cell membrane function and controlling expression of glucose metabolism genes [53]. For the past decade, there has been an influx of studies investigating the effects of n-3 PUFA on the prevention and management of type 2 diabetes [52]. But as observed in the case of CVD and cancer prevention and treatment, the evidence for a protective effect of n-3 PUFA on type 2 diabetes and its related parameters also remains inconsistent [51,52][51][52]. A SRMA of 12 RCTs studying the effects of n-3 PUFA on glucose control reported no reduction in fasting insulin (FINS), glycosylated hemoglobin (HbA1c), and HOMA of insulin resistance (HOMA-IR) levels [51]. Another SRMA of 25 RCTs investigating the effects of n-3 PUFA supplementation on type 2 diabetes treatment or prevention showed a significant reduction in fasting blood glucose and insulin resistance, but no significant effect on HbA1c was observed [52]. Trials examining the effects of n-3 PUFA on type 2 diabetes among those with impaired glucose tolerance or with metabolic syndrome also found no significant changes in HbA1c, fasting glucose, and insulin sensitivity with the doses of n-3 PUFA ranging from 0.6 to 6 g per day for a duration ranging from 8 weeks to 1 year [54,55,56,57,58][54][55][56][57][58]. Conversely, other trials reported a significant reduction in fasting blood glucose, insulin resistance, and HbA1c after supplementing the diet with dosage of n-3 PUFA ranging from 0.41 to 3 g/day for a follow-up of 8 weeks to 1 year as well [59,60,61,62,63][59][60][61][62][63]. One particular RCT conducted among patients with vitamin D deficiency reported a significant increase in HbA1c in the n-3 PUFA group after 8 weeks of supplementation with 0.3 g of n-3 PUFA daily and 50,000 IU of vitamin D weekly [64].

2.4. Macular Degeneration

Age-related macular degeneration (AMD) accounts for 8.7% of blindness globally in people 60 years and older, while the number of people with AMD is expected to increase to 288 million by 2040 [71][65]. Consumption of n-3 PUFA has been postulated as a potentially effective strategy to protect against AMD [72][66]. Evidence from prospective cohort, cross-sectional, and case-control studies has previously shown an association with intake of fatty fish consumption or n-3 PUFA and reduced risk of AMD [73,74,75][67][68][69]. A newly published dose–response meta-analysis of 11 prospective cohorts reported that an increment of 1 g of EPA + DHA daily reduced early AMD risk by 50–60% [76][70]. Conversely, a review examining high quality evidence from only two RCTs demonstrated that supplementation of n-3 PUFA for up to 5 years did not reduce the incidence or risk of progression to advanced AMD [77][71]. The Age-Related Eye Disease Study 2 (AREDS2), a large-scale study of 4203 participants with a mean age of 73.1 years and at risk for progression to advanced AMD, reported that 1 g of EPA + DHA combined with lutein and zeaxanthin did not reduce the progression to advanced AMD after a median follow-up of 5 years [78][72]. Another large-scale trial, the VITAL study found no overall effect of n-3 PUFA on AMD incidence or progression among 25,871 participants with a mean age of 67.1 years after a median follow-up of 5.3 years [79][73].

References

  1. Flock, M.R.; Harris, W.S.; Kris-Etherton, P.M. Long-chain omega-3 fatty acids: Time to establish a dietary reference intake. Nutr. Rev. 2013, 71, 692–707.
  2. Mozaffarian, D.; Wu, J.H. Omega-3 fatty acids and cardiovascular disease: Effects on risk factors, molecular pathways, and clinical events. J. Am. Coll. Cardiol. 2011, 58, 2047–2067.
  3. Weylandt, K.H.; Serini, S.; Chen, Y.Q.; Su, H.M.; Lim, K.; Cittadini, A.; Calviello, G. Omega-3 Polyunsaturated Fatty Acids: The Way Forward in Times of Mixed Evidence. Biomed. Res. Int. 2015, 2015, 143109.
  4. Tur, J.A.; Bibiloni, M.M.; Sureda, A.; Pons, A. Dietary sources of omega 3 fatty acids: Public health risks and benefits. Br. J. Nutr. 2012, 107 (Suppl. S2), S23–S52.
  5. Racey, M.; MacFarlane, A.; Carlson, S.E.; Stark, K.D.; Plourde, M.; Field, C.J.; Yates, A.A.; Wells, G.; Grantham, A.; Bazinet, R.P.; et al. Dietary Reference Intakes based on chronic disease endpoints: Outcomes from a case study workshop for omega 3’s EPA and DHA. Appl. Physiol. Nutr. Metab. 2021, 46, 530–539.
  6. Yusuf, S.; Reddy, S.; ÔUnpuu, S.; Anand, S. Global Burden of Cardiovascular Diseases. Circulation 2001, 104, 2855–2864.
  7. Lee, K.H.; Seong, H.J.; Kim, G.; Jeong, G.H.; Kim, J.Y.; Park, H.; Jung, E.; Kronbichler, A.; Eisenhut, M.; Stubbs, B.; et al. Consumption of Fish and ω-3 Fatty Acids and Cancer Risk: An Umbrella Review of Meta-Analyses of Observational Studies. Adv. Nutr. 2020, 11, 1134–1149.
  8. Khan, S.U.; Lone, A.N.; Khan, M.S.; Virani, S.S.; Blumenthal, R.S.; Nasir, K.; Miller, M.; Michos, E.D.; Ballantyne, C.M.; Boden, W.E.; et al. Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis. EClinicalMedicine 2021, 38, 100997.
  9. Xie, L.; Zhen, P.; Wei, Q.; Yu, F.; Song, S.; Tong, J. Effects of omega-3 polyunsaturated fatty acids supplementation for patients with cardiovascular disease risks: A dose-response meta-analysis. Am. J. Transl. Res. 2021, 13, 8526–8539.
  10. Aung, T.; Halsey, J.; Kromhout, D.; Gerstein, H.C.; Marchioli, R.; Tavazzi, L.; Geleijnse, J.M.; Rauch, B.; Ness, A.; Galan, P.; et al. Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks: Meta-analysis of 10 Trials Involving 77 917 Individuals. JAMA Cardiol. 2018, 3, 225–234.
  11. Hu, Y.; Hu, F.B.; Manson, J.E. Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants. J. Am. Heart Assoc. 2019, 8, e013543.
  12. Hanson, S.; Thorpe, G.; Winstanley, L.; Abdelhamid, A.S.; Hooper, L. Omega-3, omega-6 and total dietary polyunsaturated fat on cancer incidence: Systematic review and meta-analysis of randomised trials. Br. J. Cancer 2020, 122, 1260–1270.
  13. Kromhout, D.; Bosschieter, E.B.; de Lezenne Coulander, C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N. Engl. J. Med. 1985, 312, 1205–1209.
  14. Zheng, J.; Huang, T.; Yu, Y.; Hu, X.; Yang, B.; Li, D. Fish consumption and CHD mortality: An updated meta-analysis of seventeen cohort studies. Public Health Nutr. 2012, 15, 725–737.
  15. Rochon, P.A.; Gurwitz, J.H.; Sykora, K.; Mamdani, M.; Streiner, D.L.; Garfinkel, S.; Normand, S.L.; Anderson, G.M. Reader’s guide to critical appraisal of cohort studies: 1. Role and design. BMJ 2005, 330, 895–897.
  16. Shen, S.; Gong, C.; Jin, K.; Zhou, L.; Xiao, Y.; Ma, L. Omega-3 Fatty Acid Supplementation and Coronary Heart Disease Risks: A Meta-Analysis of Randomized Controlled Clinical Trials. Front. Nutr. 2022, 9, 20.
  17. Bernasconi, A.A.; Wiest, M.M.; Lavie, C.J.; Milani, R.V.; Laukkanen, J.A. Effect of Omega-3 Dosage on Cardiovascular Outcomes: An Updated Meta-Analysis and Meta-Regression of Interventional Trials. Mayo Clin. Proc. 2021, 96, 304–313.
  18. Yokoyama, M.; Origasa, H.; Matsuzaki, M.; Matsuzawa, Y.; Saito, Y.; Ishikawa, Y.; Oikawa, S.; Sasaki, J.; Hishida, H.; Itakura, H.; et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint analysis. Lancet 2007, 369, 1090–1098.
  19. Tavazzi, L.; Maggioni, A.P.; Marchioli, R.; Barlera, S.; Franzosi, M.G.; Latini, R.; Lucci, D.; Nicolosi, G.L.; Porcu, M.; Tognoni, G.; et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): A randomised, double-blind, placebo-controlled trial. Lancet 2008, 372, 1223–1230.
  20. Bhatt, D.L.; Steg, P.G.; Miller, M.; Brinton, E.A.; Jacobson, T.A.; Ketchum, S.B.; Doyle, R.T., Jr.; Juliano, R.A.; Jiao, L.; Granowitz, C.; et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N. Engl. J. Med. 2019, 380, 11–22.
  21. Marchioli, R.; Barzi, F.; Bomba, E.; Chieffo, C.; Di Gregorio, D.; Di Mascio, R.; Franzosi, M.G.; Geraci, E.; Levantesi, G.; Maggioni, A.P.; et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: Time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002, 105, 1897–1903.
  22. Galan, P.; Kesse-Guyot, E.; Czernichow, S.; Briancon, S.; Blacher, J.; Hercberg, S. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: A randomised placebo controlled trial. BMJ 2010, 341, c6273.
  23. Rauch, B.; Schiele, R.; Schneider, S.; Diller, F.; Victor, N.; Gohlke, H.; Gottwik, M.; Steinbeck, G.; Del Castillo, U.; Sack, R.; et al. OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation 2010, 122, 2152–2159.
  24. Kromhout, D.; Giltay, E.J.; Geleijnse, J.M. n–3 Fatty Acids and Cardiovascular Events after Myocardial Infarction. N. Engl. J. Med. 2010, 363, 2015–2026.
  25. Investigators, O.T.; Bosch, J.; Gerstein, H.C.; Dagenais, G.R.; Diaz, R.; Dyal, L.; Jung, H.; Maggiono, A.P.; Probstfield, J.; Ramachandran, A.; et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N. Engl. J. Med. 2012, 367, 309–318.
  26. Risk; Prevention Study Collaborative, G.; Roncaglioni, M.C.; Tombesi, M.; Avanzini, F.; Barlera, S.; Caimi, V.; Longoni, P.; Marzona, I.; Milani, V.; et al. n-3 fatty acids in patients with multiple cardiovascular risk factors. N. Engl. J. Med. 2013, 368, 1800–1808.
  27. Bonds, D.E.; Harrington, M.; Worrall, B.B.; Bertoni, A.G.; Eaton, C.B.; Hsia, J.; Robinson, J.; Clemons, T.E.; Fine, L.J.; Chew, E.Y. Effect of Long-Chain ω-3 Fatty Acids and Lutein + Zeaxanthin Supplements on Cardiovascular Outcomes. JAMA Intern. Med. 2014, 174, 763.
  28. Andrieu, S.; Guyonnet, S.; Coley, N.; Cantet, C.; Bonnefoy, M.; Bordes, S.; Bories, L.; Cufi, M.-N.; Dantoine, T.; Dartigues, J.-F.; et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): A randomised, placebo-controlled trial. Lancet Neurol. 2017, 16, 377–389.
  29. Group, A.S.C.; Bowman, L.; Mafham, M.; Wallendszus, K.; Stevens, W.; Buck, G.; Barton, J.; Murphy, K.; Aung, T.; Haynes, R.; et al. Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus. N. Engl. J. Med. 2018, 379, 1540–1550.
  30. Manson, J.E.; Cook, N.R.; Lee, I.M.; Christen, W.; Bassuk, S.S.; Mora, S.; Gibson, H.; Albert, C.M.; Gordon, D.; Copeland, T.; et al. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N. Engl. J. Med. 2019, 380, 23–32.
  31. Nicholls, S.J.; Lincoff, A.M.; Garcia, M.; Bash, D.; Ballantyne, C.M.; Barter, P.J.; Davidson, M.H.; Kastelein, J.J.P.; Koenig, W.; McGuire, D.K.; et al. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA 2020, 324, 2268–2280.
  32. Kalstad, A.A.; Myhre, P.L.; Laake, K.; Tveit, S.H.; Schmidt, E.B.; Smith, P.; Nilsen, D.W.T.; Tveit, A.; Fagerland, M.W.; Solheim, S.; et al. Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction. Circulation 2021, 143, 528–539.
  33. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J. Clin. 2021, 71, 209–249.
  34. Diggle, C.P. In vitro studies on the relationship between polyunsaturated fatty acids and cancer: Tumour or tissue specific effects? Prog. Lipid Res. 2002, 41, 240–253.
  35. Gleissman, H.; Johnsen, J.I.; Kogner, P. Omega-3 fatty acids in cancer, the protectors of good and the killers of evil? Exp. Cell Res. 2010, 316, 1365–1373.
  36. Engeset, D.; Alsaker, E.; Lund, E.; Welch, A.; Khaw, K.-T.; Clavel-Chapelon, F.; Thiébaut, A.; Chajès, V.; Key, T.J.; Allen, N.E.; et al. Fish consumption and breast cancer risk. The European Prospective Investigation into Cancer and Nutrition (EPIC). Int. J. Cancer 2006, 119, 175–182.
  37. Nindrea, R.D.; Aryandono, T.; Lazuardi, L.; Dwiprahasto, I. Protective Effect of Omega-3 Fatty Acids in Fish Consumption Against Breast Cancer in Asian Patients: A Meta-Analysis. Asian Pac. J. Cancer Prev. 2019, 20, 327–332.
  38. Ziegler, R.G.; Hoover, R.N.; Pike, M.C.; Hildesheim, A.; Nomura, A.M.; West, D.W.; Wu-Williams, A.H.; Kolonel, L.N.; Horn-Ross, P.L.; Rosenthal, J.F.; et al. Migration patterns and breast cancer risk in Asian-American women. J. Natl. Cancer Inst. 1993, 85, 1819–1827.
  39. Terry, P.D.; Rohan, T.E.; Wolk, A. Intakes of fish and marine fatty acids and the risks of cancers of the breast and prostate and of other hormone-related cancers: A review of the epidemiologic evidence. Am. J. Clin. Nutr. 2003, 77, 532–543.
  40. Gago-Dominguez, M.; Yuan, J.M.; Sun, C.L.; Lee, H.P.; Yu, M.C. Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: The Singapore Chinese Health Study. Br. J. Cancer 2003, 89, 1686–1692.
  41. Yang, B.; Ren, X.L.; Wang, Z.Y.; Wang, L.; Zhao, F.; Guo, X.J.; Li, D. Biomarker of long-chain n-3 fatty acid intake and breast cancer: Accumulative evidence from an updated meta-analysis of epidemiological studies. Crit. Rev. Food Sci. Nutr. 2019, 59, 3152–3164.
  42. Zhang, Y.-F.; Gao, H.-F.; Hou, A.-J.; Zhou, Y.-H. Effect of omega-3 fatty acid supplementation on cancer incidence, non-vascular death, and total mortality: A meta-analysis of randomized controlled trials. BMC Public Health 2014, 14, 204.
  43. de Lorgeril, M.; Salen, P.; Martin, J.L.; Monjaud, I.; Boucher, P.; Mamelle, N. Mediterranean dietary pattern in a randomized trial: Prolonged survival and possible reduced cancer rate. Arch. Intern. Med. 1998, 158, 1181–1187.
  44. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999, 354, 447–455.
  45. Bordeleau, L.; Yakubovich, N.; Dagenais, G.R.; Rosenstock, J.; Probstfield, J.; Chang Yu, P.; Ryden, L.E.; Pirags, V.; Spinas, G.A.; Birkeland, K.I.; et al. The Association of Basal Insulin Glargine and/or n-3 Fatty Acids With Incident Cancers in Patients With Dysglycemia. Diabetes Care 2014, 37, 1360–1366.
  46. Andreeva, V.A.; Touvier, M.; Kesse-Guyot, E.; Julia, C.; Galan, P.; Hercberg, S. B Vitamin and/or ω-3 Fatty Acid Supplementation and Cancer. Arch. Intern. Med. 2012, 172, 540–547.
  47. von Schacky, C.; Angerer, P.; Kothny, W.; Theisen, K.; Mudra, H. The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 1999, 130, 554–562.
  48. Brouwer, I.A.; Zock, P.L.; Camm, A.J.; Bocker, D.; Hauer, R.N.; Wever, E.F.; Dullemeijer, C.; Ronden, J.E.; Katan, M.B.; Lubinski, A.; et al. Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: The Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA 2006, 295, 2613–2619.
  49. Raitt, M.H.; Connor, W.E.; Morris, C.; Kron, J.; Halperin, B.; Chugh, S.S.; McClelland, J.; Cook, J.; MacMurdy, K.; Swenson, R.; et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: A randomized controlled trial. JAMA 2005, 293, 2884–2891.
  50. Saeedi, P.; Petersohn, I.; Salpea, P.; Malanda, B.; Karuranga, S.; Unwin, N.; Colagiuri, S.; Guariguata, L.; Motala, A.A.; Ogurtsova, K.; et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res. Clin. Pract. 2019, 157, 107843.
  51. Gao, C.; Liu, Y.; Gan, Y.; Bao, W.; Peng, X.; Xing, Q.; Gao, H.; Lai, J.; Liu, L.; Wang, Z.; et al. Effects of fish oil supplementation on glucose control and lipid levels among patients with type 2 diabetes mellitus: A Meta-analysis of randomized controlled trials. Lipids Health Dis. 2020, 19, 1–10.
  52. Delpino, F.M.; Figueiredo, L.M.; Da Silva, B.G.C.; Da Silva, T.G.; Mintem, G.C.; Bielemann, R.M.; Gigante, D.P. Omega-3 supplementation and diabetes: A systematic review and meta-analysis. Crit. Rev. Food Sci. Nutr. 2021, 62, 4435–4448.
  53. Oh, P.C.; Koh, K.K.; Sakuma, I.; Lim, S.; Lee, Y.; Lee, S.; Lee, K.; Han, S.H.; Shin, E.K. Omega-3 fatty acid therapy dose-dependently and significantly decreased triglycerides and improved flow-mediated dilation, however, did not significantly improve insulin sensitivity in patients with hypertriglyceridemia. Int. J. Cardiol. 2014, 176, 696–702.
  54. Sirtori, C.R.; Paoletti, R.; Mancini, M.; Crepaldi, G.; Manzato, E.; Rivellese, A.; Pamparana, F.; Stragliotto, E. N-3 fatty acids do not lead to an increased diabetic risk in patients with hyperlipidemia and abnormal glucose tolerance. Italian Fish Oil Multicenter Study. Am. J. Clin. Nutr. 1997, 65, 1874–1881.
  55. Manning, P.J.; Sutherland, W.H.; Williams, S.M.; Walker, R.J.; Berry, E.A.; De Jong, S.A.; Ryalls, A.R. The effect of lipoic acid and vitamin E therapies in individuals with the metabolic syndrome. Nutr. Metab. Cardiovasc. Dis. 2013, 23, 543–549.
  56. Clark, L.F.; Thivierge, M.C.; Kidd, C.A.; McGeoch, S.C.; Abraham, P.; Pearson, D.W.M.; Horgan, G.W.; Holtrop, G.; Thies, F.; Lobley, G.E. Fish oil supplemented for 9 months does not improve glycaemic control or insulin sensitivity in subjects with impaired glucose regulation: A parallel randomised controlled trial. Br. J. Nutr. 2016, 115, 75–86.
  57. Sawada, T.; Tsubata, H.; Hashimoto, N.; Takabe, M.; Miyata, T.; Aoki, K.; Yamashita, S.; Oishi, S.; Osue, T.; Yokoi, K.; et al. Effects of 6-month eicosapentaenoic acid treatment on postprandial hyperglycemia, hyperlipidemia, insulin secretion ability, and concomitant endothelial dysfunction among newly-diagnosed impaired glucose metabolism patients with coronary artery disease. An open label, single blinded, prospective randomized controlled trial. Cardiovasc. Diabetol. 2016, 15, 1–14.
  58. Javidi, A.; Mozaffari-Khosravi, H.; Nadjarzadeh, A.; Dehghani, A.; Eftekhari, M.H. The effect of flaxseed powder on insulin resistance indices and blood pressure in prediabetic individuals: A randomized controlled clinical trial. J. Res. Med. Sci. 2016, 21, 70.
  59. Derosa, G.; Cicero, A.F.G.; Fogari, E.; D’Angelo, A.; Bonaventura, A.; Maffioli, P. Effects of n-3 PUFA on insulin resistance after an oral fat load. Eur. J. Lipid Sci. Technol. 2011, 113, 950–960.
  60. Derosa, G.; Cicero, A.F.; D’Angelo, A.; Borghi, C.; Maffioli, P. Effects of n-3 pufas on fasting plasma glucose and insulin resistance in patients with impaired fasting glucose or impaired glucose tolerance. Biofactors 2016, 42, 316–322.
  61. Wang, J.F.; Zhang, H.M.; Li, Y.Y.; Xia, S.; Wei, Y.; Yang, L.; Wang, D.; Ye, J.J.; Li, H.X.; Yuan, J.; et al. A combination of omega-3 and plant sterols regulate glucose and lipid metabolism in individuals with impaired glucose regulation: A randomized and controlled clinical trial. Lipids Health Dis. 2019, 18, 106.
  62. Rajabi-Naeeni, M.; Dolatian, M.; Qorbani, M.; Vaezi, A.A. The effect of omega-3 and vitamin D co-supplementation on glycemic control and lipid profiles in reproductive-aged women with pre-diabetes and hypovitaminosis D: A randomized controlled trial. Diabetol. Metab. Syndr. 2020, 12, 41.
  63. Diaz-Rizzolo, D.A.; Serra, A.; Colungo, C.; Sala-Vila, A.; Siso-Almirall, A.; Gomis, R. Type 2 diabetes preventive effects with a 12-months sardine-enriched diet in elderly population with prediabetes: An interventional, randomized and controlled trial. Clin. Nutr. 2021, 40, 2587–2598.
  64. Barham, A.; Mohammad, B.; Hasoun, L.; Awwad, S.; Mosleh, I.; Aljaberi, A.; Abu-Samak, M. The combination of omega-3 fatty acids with high doses of vitamin D3 elevate A1c levels: A randomized Clinical Trial in people with vitamin D deficiency. Int. J. Clin. Pract. 2021, 75, e14779.
  65. Wong, W.L.; Su, X.; Li, X.; Cheung, C.M.G.; Klein, R.; Cheng, C.-Y.; Wong, T.Y. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob. Health 2014, 2, e106–e116.
  66. Akuffo, K.O.; Beatty, S.; Stack, J.; Dennison, J.; O’Regan, S.; Meagher, K.A.; Peto, T.; Nolan, J. Central Retinal Enrichment Supplementation Trials (CREST): Design and methodology of the CREST randomized controlled trials. Ophthalmic Epidemiol. 2014, 21, 111–123.
  67. Parekh, N.; Chappell, R.J.; Millen, A.E.; Albert, D.M.; Mares, J.A. Association between vitamin D and age-related macular degeneration in the Third National Health and Nutrition Examination Survey, 1988 through 1994. Arch. Ophthalmol. 2007, 125, 661–669.
  68. Smith, W.; Mitchell, P.; Leeder, S.R. Dietary fat and fish intake and age-related maculopathy. Arch. Ophthalmol. 2000, 118, 401–404.
  69. Seddon, J.M.; Rosner, B.; Sperduto, R.D.; Yannuzzi, L.; Haller, J.A.; Blair, N.P.; Willett, W. Dietary fat and risk for advanced age-related macular degeneration. Arch. Ophthalmol. 2001, 119, 1191–1199.
  70. Zhong, Y.; Wang, K.; Jiang, L.; Wang, J.; Zhang, X.; Xu, J.; Yao, K. Dietary fatty acid intake, plasma fatty acid levels, and the risk of age-related macular degeneration (AMD): A dose-response meta-analysis of prospective cohort studies. Eur. J. Nutr. 2021, 60, 3013–3027.
  71. Lawrenson, J.G.; Evans, J.R. Omega 3 fatty acids for preventing or slowing the progression of age-related macular degeneration. Cochrane Database Syst. Rev. 2015, 2015, CD010015.
  72. Age-Related Eye Disease Study 2 Research, G. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: The Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA 2013, 309, 2005–2015.
  73. Christen, W.G.; Cook, N.R.; Manson, J.E.; Buring, J.E.; Chasman, D.I.; Lee, I.M.; Bubes, V.; Li, C.; Haubourg, M.; Schaumberg, D.A.; et al. Effect of Vitamin D and omega-3 Fatty Acid Supplementation on Risk of Age-Related Macular Degeneration: An Ancillary Study of the VITAL Randomized Clinical Trial. JAMA Ophthalmol. 2020, 138, 1280–1289.
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