Effects of n−3 Fatty Acid Supplements in Diabetes Mellitus
Open accessAbstract
BACKGROUND: Increased intake of n-3 fatty acids has been associated with a reduced risk of cardiovascular disease in observational studies, but this finding has not been confirmed in randomized trials. It remains unclear whether n-3 (also called omega-3) fatty acid supplementation has cardiovascular benefit in patients with diabetes mellitus. METHODS: We randomly assigned 15,480 patients with diabetes but without evidence of atherosclerotic cardiovascular disease to receive 1-g capsules containing either n-3 fatty acids (fatty acid group) or matching placebo (olive oil) daily. The primary outcome was a first serious vascular event (i.e., nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death, excluding confirmed intracranial hemorrhage). The secondary outcome was a first serious vascular event or any arterial revascularization. RESULTS: During a mean follow-up of 7.4 years (adherence rate, 76%), a serious vascular event occurred in 689 patients (8.9%) in the fatty acid group and in 712 (9.2%) in the placebo group (rate ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.55). The composite outcome of a serious vascular event or revascularization occurred in 882 patients (11.4%) and 887 patients (11.5%), respectively (rate ratio, 1.00; 95% CI, 0.91 to 1.09). Death from any cause occurred in 752 patients (9.7%) in the fatty acid group and in 788 (10.2%) in the placebo group (rate ratio, 0.95; 95% CI, 0.86 to 1.05). There were no significant between-group differences in the rates of nonfatal serious adverse events. CONCLUSIONS: Among patients with diabetes without evidence of cardiovascular disease, there was no significant difference in the risk of serious vascular events between those who were assigned to receive n-3 fatty acid supplementation and those who were assigned to receive placebo. (Funded by the British Heart Foundation and others; Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).
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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 [32]
The participant-flow figures in the Effects on Cancer and Other Nonvascular Outcomes section report 121,254 people assessed for eligibility and 15,480 randomized in ASCEND—about 13%. On that screened-candidate basis, ASCEND’s inclusion rate was lower, not higher, than the stated 26% for OMEMI. The source does not report OMEMI’s own inclusion rate. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe 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 [100]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredClinical trials revealed that omega-3 PUFA supplementation of <1 g/d resulted in a very limited reduction in atherosclerotic CVD risk of major vascular events and CVD-caused deaths.
“Clinical trials revealed that ω3 PUFA supplementation of <1 g/d resulted in a very limited reduction in atherosclerotic CVD risk of major vascular events and CVD‐caused deaths. 22 , 23 , 133 , 154”
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 [133]
The Procedures section describes a daily capsule containing 840 mg of n−3 fatty acids, below 1 g. The Primary and Secondary Outcomes section reports a small, nonsignificant difference in serious vascular events (8.9% versus 9.2%) and fewer vascular deaths only in exploratory analyses. Thus the paper supports limited evidence of benefit, but not the claim that supplementation established a reduction in both outcomes. (LLM, conf=0.85)
Experimental — accuracy not yet measuredEarlier trials GISSI-Prevenzione, ASCEND, VITAL, and OMEMI evaluated low-dose EPA/DHA mixtures primarily in primary prevention settings or post-MI patients, often without significant baseline TG elevation and with limited use of statins in earlier trials.
“Earlier trials such as GISSI-Prevenzione, ASCEND, VITAL, and OMEMI evaluated low-dose EPA/DHA mixtures primarily in primary prevention settings or post-MI patients, often without significant baseline TG elevation and with limited use of statins in earlier trials [87–90].”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [88]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAcross several major RCTs (REDUCE-IT, RESPECT-EPA, GISSI-HF, ASCEND), the magnitude of CV benefit equaled or exceeded the observed increase in AF risk.
“Across several major RCTs, such as REDUCE-IT69, 125, RESPECT-EPA76, GISSI-HF77 and ASCEND79, 105; the magnitude of CV benefit equaled or exceeded the observed increase in AF risk.”
From Effects of Omega-3 Fatty Acid Treatment on Risk for Atrial Fibrillation: An Updated Meta-Analysis of 35 Trials including 114 592 Individuals (2026) · cites this paper as [79]
The paper identifies ASCEND as a randomized trial and reports fewer vascular deaths in an exploratory analysis (Primary and Secondary Outcomes; page not provided). But it found no significant reduction in serious vascular events, and our copy does not report an increase in atrial fibrillation risk or compare that risk with cardiovascular benefit. The claimed benefit–risk comparison for ASCEND is therefore unsupported. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Other recent trials studying lower doses of omega-3 fatty acids in a broader range of patients failed to demonstrate significant reductions of total cardiovascular events.
“However, other recent trials studying lower doses of omega-3 fatty acids in a broader range of patients failed to demonstrate significant reductions of total cardiovascular events. 12,13”
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 [12]
Several large clinical trials failed to demonstrate any cardiovascular benefit with administration of low doses of omega-3 fatty acids.
“butseverallargeclinicaltrialsfailed to demonstrate any cardiovascular benefit with administration of low doses of omega-3 fatty acids. 8,12,13”
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 [12]
These earlier trials showed inconsistent reductions in MACE.
“These studies showed inconsistent reductions in MACE.”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [88]
The ASCEND and VITAL trials using EPA+DHA did not significantly reduce the primary cardiovascular endpoints.
“The ASCEND (A Study of Cardiovascular Events in Diabetes) [3] and VITAL (Vitamin D and Omega-3 Trial) trials [5] using EPA+DHA did not signi fi cantly reduce the primary cardiovascular endpoints”
From Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis (2021) · cites this paper as [3]
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 [9]
Contemporary ω-3 fatty acid trials were conducted with higher standards and consistently failed to demonstrate significant cardiovascular benefits.
“Contemporary studies were conducted with higher standards and consistently failed to demonstrate significant benefits.”
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 [87]
Two recent meta-analyses reported no overall benefit of fibrates.
“No overall benefit was reported in two recent meta-analyses [312,313].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [313]
A subsequent randomized controlled trial in patients with diabetes without evidence of atherosclerotic cardiovascular disease supported that fish oil dietary supplementation does not alter the risk of serious cardiovascular events as primary prevention in that group.
“a subsequently reported randomized, controlled trial in patients with diabetes without evidence of atherosclerotic cardiovascular disease further supported that fish oil dietary supplementation does not alter the risk of serious cardiovascular events when used as a primary prevention strategy, at least in this group of patients123.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [123]
In exploratory ASCEND analyses, vascular deaths were fewer by 19% relative risk reduction and this reached statistical significance.
“In exploratory analyses, there were fewer vascular deaths (19% relative risk reduction) that achieved statistical significance.”
From Cardiovascular Impact of Nutritional Supplementation With Omega-3 Fatty Acids (2021) · cites this paper as [60]
In the statin era, cardiovascular outcomes trials of combination omega-3 fatty acids (EPA and DHA) have not shown reduction in cardiovascular disease events.
“In the statin era, CVOTs of combination OM-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] have not shown reduction in cardiovascular disease (CVD) events.”
From Critical Differences Between Dietary Supplement and Prescription Omega-3 Fatty Acids: A Narrative Review (2020) · cites this paper as [10]
Additional factors that may influence cardiovascular outcomes trial findings include omega-3 dose, definition of primary composite cardiovascular endpoint, and study population.
“Additional factors that may influence CVOT findings include OM-3 dose, definition of primary composite CV endpoint, and study population.”
From Critical Differences Between Dietary Supplement and Prescription Omega-3 Fatty Acids: A Narrative Review (2020) · cites this paper as [10]
The primary composite cardiovascular endpoint varied between the recent omega-3 cardiovascular outcomes trials.
“The primary composite CV endpoint varied between the studies (Table 1, see footnote); for example, in REDUCE-IT, coronary revascularization and unstable angina were included, in addition to CV death, nonfatal myocardial infarction, and nonfatal stroke.”
From Critical Differences Between Dietary Supplement and Prescription Omega-3 Fatty Acids: A Narrative Review (2020) · cites this paper as [10]
The total daily dose of omega-3 was much lower in VITAL and ASCEND (<1 g/day total omega-3 per each 1-g capsule) than in REDUCE-IT (4 g/day high-purity prescription EPA).
“The total daily dose of OM-3 was much lower in VITAL and ASCEND (< 1 g/day total OM-3 per each 1-g capsule) than in REDUCE-IT (4 g/day high-purity Rx EPA).”
From Critical Differences Between Dietary Supplement and Prescription Omega-3 Fatty Acids: A Narrative Review (2020) · cites this paper as [10]
In the ASCEND trial, supplementation with n-3 fatty acids at 1 g/day did not lead to cardiovascular benefit in people with diabetes without evidence of CVD compared with placebo.
“In the ASCEND trial (A Study of Cardiovascular Events iN Diabetes), when compared with placebo, supplementation with n-3 fatty acids at the dose of 1 g/day did not lead to cardiovascular benefit in people with diabetes without evidence of CVD (212).”
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 [212]
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“…Therapy–Statin and Eicosapentae-noic Acid), 76 GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca), 77 and ASCEND (A Study of Cardiovascular Events in Diabetes) 6,79 ; the magnitude of cardiovascular benefit equaled or exceeded the observed increase in AF risk.”
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“Our initial manuscript included Trials such as ORIGIN [8] , ASCEND [9] , Alpha Omega [10] , and JELIS [5] ; 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 signi fi cant studies.”
- Authors
- The ASCEND Study Collaborative Group
- Affiliations
- MRC Population Health Research Unit (GB)
- Corresponding author
- The ASCEND Study Collaborative Group
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-10-18
- Volume
- 379
- Issue
- 16
- Pages
- 1540-1550
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2900151286
- Semantic Scholar
- e0637ff6c08882f0e8168685449286ad38f70179
- Cited by
- 698
- References
- 28
- Citations by year
- 2026: 56 · 2025: 54 · 2024: 58 · 2023: 92 · 2022: 89 · 2021: 100 · 2020: 119 · 2019: 105 · 2018: 23 · 2017: 1 · 2014: 1
- FWCI
- 71.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Solvay
- Mylan
- Bayer U.S.
- British Heart Foundation (SP/03/02, SP/08/010/25939, SP/14/1331114)
- 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 › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- omega-3 fatty acids, omega-3 supplementation, diabetes mellitus, cardiovascular events, myocardial infarction, stroke, vascular revascularization, mortality, olive oil placebo, cardiovascular risk
- MeSH terms
- Adult, Aged, Aspirin, Cardiovascular Diseases, Diabetes Mellitus, Female, Follow-Up Studies, Humans, Male, Middle Aged, Platelet Aggregation Inhibitors, Fatty Acids, Omega-3, Treatment Outcome, Dietary Supplements, Diabetes Complications, Kaplan-Meier Estimate
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