Association of circulating fatty acids with cardiovascular disease risk: analysis of individual-level data in three large prospective cohorts and updated meta-analysis
- PMID: 39365172
- PMCID: PMC11832215
- DOI: 10.1093/eurjpc/zwae315
Association of circulating fatty acids with cardiovascular disease risk: analysis of individual-level data in three large prospective cohorts and updated meta-analysis
Abstract
Aims: Associations of saturated and unsaturated fatty acids (FAs) with cardiovascular disease (CVD) remain controversial. We therefore aimed to investigate the prospective associations of objectively measured FAs with CVD, including incident coronary heart disease (CHD) and stroke, as well as CVD mortality.
Methods and results: Circulating FA concentrations expressed as the percentage of total FAs were assayed in 172 891 participants without prior vascular disease at baseline from the European Prospective Investigation into Cancer and Nutrition-CVD (EPIC-CVD) (7343 CHD; 6499 stroke), UK Biobank (1825; 1474), and INTERVAL (285; 209) cohort studies. Hazard ratio (HR) per 1-standard deviation (SD) higher FA concentrations was estimated using Cox regression models and pooled by random-effects meta-analysis. Systematic reviews with meta-analysis published by 6 May 2023 on associations between FAs and CVDs were systematically searched and updated meta-analyses using random-effects model were conducted. Evidence from randomized controlled trials (RCTs) was also summarized. Higher concentrations of total saturated FAs (SFAs) were associated with higher cardiovascular risks in the combined analysis, with differential findings noted for SFA sub-types in further analysis restricted to EPIC-CVD: positive associations for even-chain SFA [HR for CHD 1.24 (95% CI: 1.18-1.32); stroke 1.23 (1.10-1.38)] and negative associations for odd-chain [0.82 (0.76-0.87); 0.73 (0.67-0.78)] and longer-chain [0.95 (0.80-1.12); 0.84 (0.72-0.99)] SFA. In the combined analysis, total n-3 polyunsaturated FA (PUFA) [0.91 (0.85-0.97)], including docosahexaenoic acid (DHA) [0.91 (0.84-0.98)], was negatively associated with incident CHD risk. Similarly, total n-6 PUFA [0.94 (0.91-0.98)], including linoleic acid (LA) [0.89 (0.83-0.95)], was negatively associated with incident stroke risk. In contrast, more detailed analyses in EPIC-CVD revealed that several downstream n-6 PUFAs of LA were positively associated with CHD risk. Updated meta-analyses of 37 FAs including 49 non-overlapping studies, involving between 7787 and 22 802 CHD cases and between 6499 and 14 221 stroke cases, showed broadly similar results as our combined empirical analysis and further suggested significant inverse associations of individual long-chain n-3 PUFAs and LA on both CHD and stroke. The findings of long-chain n-3 PUFAs were consistent with those from published RCTs on CHD despite insufficient evidence in monotherapy, while RCT evidence remained unclear for the rest of the explored FAs.
Conclusion: Our study provides an overview of the most recent evidence on the associations between objectively measured FAs and CVD outcomes. Collectively, the data reveal notable differences in associations by SFA sub-types and call for further studies, especially RCTs, to explore these links.
Keywords: Cardiovascular disease; Cohort study; Coronary heart disease; Fatty acids; Meta-analysis; Stroke.
Plain language summary
We conducted the largest analysis to date to examine the association of circulating saturated and unsaturated fatty acids, either individually or in combination, with incident cardiovascular disease (CVD) outcomes.Our study reinforces that CVD associations vary importantly across saturated fatty acid sub-types, with positive associations for even-chain saturated fatty acids but negative associations for odd-chain and longer-chain saturated fatty acids, challenging the current broad dietary recommendations focused solely on lowering overall saturated fat intake.Marine-derived n-3 polyunsaturated fatty acids and linoleic acid were negatively associated with both coronary heart disease and stroke, except for eicosapentaenoic acid, which was null for stroke. It supports the potential cardiovascular benefits of individual marine-derived n-3 polyunsaturated fatty acids and linoleic acid and provides evidence to help inform currently inconsistent and insufficient trial evidence.
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.
Conflict of interest statement
Conflict of interest: E.S. and L.S. contributed to this work while employed full-time by the University of Cambridge, but are currently employed full-time by AstraZeneca PLC (E.S.) and Regeneron Genetics Center LLC (L.S.). T.Y.N.T. for grant support from Medical Research Council (MR/M012190/1) and UK Research and Innovation (MR/X032809/1); N.F. for reimbursement of travel expenses for meetings of the EAT-Lancet Commission on food, health and planetary sustainability; J.D. for grants outside of present manuscript from Astra Zeneca, Merck Sharp & Dohme Corporation and Novartis; and A.S.B. for grants outside of this work from AstraZeneca, Bayer, BioMarin, Regeneron and Sanofi. J.D. stated other relationships, interests, or activities, including Cambridge University Hospital NHS Foundation Trust (Honorary Consultant), UK Biobank (Steering Committee), MRC International Advisory Group (Member), MRC High Throughput Science ‘Omics Panel (Member), Scientific Advisory Committee for Sanofi (Member), Wellcome Sanger Institute (Faculty Member) and Novartis (Advisor).
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Comment in
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Saturated vs. unsaturated fatty acids: should we reconsider their cardiovascular effects?Eur J Prev Cardiol. 2025 Feb 18;32(3):247-248. doi: 10.1093/eurjpc/zwae340. Eur J Prev Cardiol. 2025. PMID: 39509275 No abstract available.
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- Krauss RM, Kris-Etherton PM. Public health guidelines should recommend reducing saturated fat consumption as much as possible: debate consensus. Am J Clin Nutr 2020;112:25–26. - PubMed
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