n–3 Fatty Acids and Cardiovascular Outcomes in Patients with Dysglycemia
Open accessAbstract
BACKGROUND: The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infarction or heart failure. Their effects in patients with (or at risk for) type 2 diabetes mellitus are unknown. METHODS: In this double-blind study with a 2-by-2 factorial design, we randomly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes to receive a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or standard care. The primary outcome was death from cardiovascular causes. The results of the comparison between n-3 fatty acids and placebo are reported here. RESULTS: During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72). The use of n-3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients [16.5%] vs. 1017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P=0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P=0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P=0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n-3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups. CONCLUSIONS: Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.).
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Even among omega-3 fatty acid studies, there are marked differences with respect to the relatively low doses of omega-3 administered and the ratio of EPA to DHA.
“Even among omega‐3 fatty acid studies, there are marked differences with respect to the relatively low doses of omega‐3 administered and the ratio of EPA to DHA.16, 17, 18, 19, 20, 21, 22, 23, 24”
From Rationale and design of <scp>REDUCE‐IT</scp> : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [21]
The Randomization, Study Intervention, and Follow-up section specifies this trial’s 1-g dose and its EPA and DHA amounts. The Discussion says doses tested across trials ranged from 0.4 g to 4.8 g, supporting variation in dose, but our copy does not establish that EPA-to-DHA ratios differed across studies. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn the ORIGIN trial, administration of 1 g/day of combined EPA + DHA (465 mg EPA and 375 mg DHA) had no impact on cardiovascular mortality in more than 12,000 patients with impaired fasting glucose and at high risk for cardiovascular events.
“In the ORIGIN trial, which enrolled more than 12,000 patients with impaired fasting glucose and at high risk for cardiovascular events, the administration of 1 g/day of combined EPA + DHA (465 mg of EPA and 375 mg of DHA) had no impact on cardiovascular mortality [89].”
From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [89]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredMany previous and recently completed clinical studies showed that ω3 PUFA supplementation did not offer significant favorable impacts on cardiovascular events.
“However, many previous 20 , 21 , 22 , 23 and recently completed clinical studies 24 , 25 showed that ω3 PUFA supplementation did not offer significant favorable impacts on cardiovascular events.”
From Association Between Omega-3 Fatty Acid Intake and Dyslipidemia: A Continuous Dose-Response Meta-Analysis of Randomized Controlled Trials (2023) · cites this paper as [20]
The STRENGTH, VITAL, ASCEND, ORIGIN, OMEGA, ALPHA-OMEGA, GISSI-HF and GISSI-P trials randomized patients to receive either a combination of EPA and DHA or placebo; yet only the GISSI trials noted a statistically significant effect on cardiovascular events and mortality.
“The STRENGTH, VITAL, ASCEND, ORIGIN, OMEGA, ALPHA-OMEGA, GISSI-HF and GISSI-P trials randomized patients to receive either a combination of EPA and DHA or placebo; yet only the GISSI trials noted a statistically significant effect on cardiovascular events and mortality [96–103].”
From Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention (2023) · cites this paper as [99]
Subsequent larger trials failed to replicate the cardiovascular benefit findings of the earlier EPA and DHA supplement study.
“but subsequent larger trials failed to replicate these findings. 8,9”
From Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk (2020) · cites this paper as [9]
The dosage used in OMEMI was about twice that used in comparable earlier trials, but considerably lower than the dosage used in REDUCE-IT and STRENGTH.
“Nevertheless, the dosage used in OMEMI was about twice that used in comparable earlier trials 5, 7, 23, 30 , although considerably lower than the dosage used in REDUCE-IT 14 , and also in the STRENGTH trial 36 .”
From Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction (2021) · cites this paper as [30]
The inclusion rate in OMEMI was 26% of screened candidates, which is relatively low compared to other n-3 PUFA trials not targeting elderly patients.
“A limitation to the study is the inclusion rate of 26 % of screened candidates, which is relatively low compared to other n-3 PUFA trials not targeting elderly patients 30-33 .”
From Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction (2021) · cites this paper as [30]
More recent omega-3 therapy outcome studies conducted in the presence of statins have been less encouraging, but evaluated nonhypertriglyceridemic patient populations and administered low doses of long-chain omega-3 fatty acids.
“Other more recent omega‐3 therapy outcome studies conducted in the presence of statins have been less encouraging, but these studies were characterized by evaluating nonhypertriglyceridemic patient populations (eg, TG <200 mg/dL) and administering low doses of long‐chain omega‐3 fatty acids (eg, eicosapentaenoic acid [EPA] and/or docosoahexaenoic acid [DHA]).19, 20, 21, 22, 23, 24”
From Rationale and design of <scp>REDUCE‐IT</scp> : Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (2017) · cites this paper as [21]
The initial manuscript's results were skewed because its search strategy missed significant studies and included trials that mostly used EPA and DHA combinations rather than IPE.
“Our initial manuscript included Trials such as ORIGIN8, ASCEND9, Alpha Omega10, and JELIS5; among these trials, only one trial had IPE, and the rest of the trials had a combination of EPA and DHA, so our results were skewed as search strategy missed significant studies.”
From Cardiovascular outcomes and coronary artery disease prevention secondary to icosapent ethyl: a meta-analysis of randomized clinical trials (2024) · cites this paper as [8]
Data from studies on n-3 fatty acid supplementation do not support recommending n-3 fatty acid supplements for secondary prevention of cardiovascular disease in type 2 diabetes.
“Data from studies on supplementation with n-3 fatty acids do not support recommending n-3 fatty acid supplements for secondary prevention of CVD in T2DM.86,87”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [86]
In the ORIGIN trial, after a median follow-up of 6.2 years, the incidence of cardiovascular outcomes did not differ between insulin glargine and standard care in patients at high cardiovascular risk with impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes.
“In the ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial, 12 537 patients (mean age 63.5 years) at high CVD risk with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or T2DM were randomized to insulin glargine titrated to a fasting blood glucose level of ≤5.3 mmol/L (≤95 mg/dL) or standard care.86 After a median follow-up of 6.2 years, the incidence of CV”
From 2023 ESC guidelines for the management of cardiovascular disease in patients with diabetes. (2023) · cites this paper as [86]
The JELIS study found that adding EPA to statins showed a significant preventive effect on major cardiovascular events compared with statin monotherapy.
“The JELIS study692) conducted in Japan found that the addition of EPA to statins showed a significant preventive effect on major cardiovascular events compared to statin monotherapy.”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [692]
Evidence does not conclusively support recommending n-3 supplements for all people with diabetes for the prevention or treatment of cardiovascular events.
“Evidence does not conclusively support recommending n-3 (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) supplements for all people with diabetes for the prevention or treatment of cardiovascular events (70,209,210).”
From 5. Facilitating Positive Health Behaviors and Well-being to Improve Health Outcomes:<i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [210]
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- Authors
- The ORIGIN Trial Investigators
- Corresponding author
- The ORIGIN Trial Investigators
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-07-26
- Volume
- 367
- Issue
- 4
- Pages
- 309-318
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W1560062315
- Semantic Scholar
- 00cc8344ced92b3c8921b97df8607e6b3032e111
- Cited by
- 929
- References
- 21
- Citations by year
- 2026: 19 · 2025: 23 · 2024: 41 · 2023: 53 · 2022: 51 · 2021: 57 · 2020: 76 · 2019: 60 · 2018: 72 · 2017: 56 · 2016: 90 · 2015: 79 · 2014: 90 · 2013: 122 · 2012: 38
- FWCI
- 97.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- Monash University Research Portal (Monash University) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- HAL (submittedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- IRIS (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- omega-3 fatty acids, cardiovascular outcomes, type 2 diabetes, dysglycemia, impaired fasting glucose, impaired glucose tolerance, insulin glargine, cardiovascular mortality, major vascular events, triglycerides, serum lipids, cardiac arrhythmias, cardiovascular risk reduction, dietary supplementation, omega-3 fatty acid ethyl esters
- MeSH terms
- Insulin Glargine, Aged, Cardiovascular Diseases, Cholesterol, Diabetes Mellitus, Type 2, Double-Blind Method, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Hypoglycemic Agents, Male, Middle Aged, Triglycerides, Fatty Acids, Omega-3, Incidence, Proportional Hazards Models, Treatment Failure, Glucose Intolerance, Insulin, Long-Acting, Intention to Treat Analysis
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