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Association between pre-diagnostic circulating lipid metabolites and colorectal cancer risk: a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC).
Harewood, R, Rothwell, JA, Bešević, J, Viallon, V, Achaintre, D, Gicquiau, A, Rinaldi, S, Wedekind, R, Prehn, C, Adamski, J, et al
EBioMedicine. 2024;:105024
Abstract
BACKGROUND Altered lipid metabolism is a hallmark of cancer development. However, the role of specific lipid metabolites in colorectal cancer development is uncertain. METHODS In a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined associations between pre-diagnostic circulating concentrations of 97 lipid metabolites (acylcarnitines, glycerophospholipids and sphingolipids) and colorectal cancer risk. Circulating lipids were measured using targeted mass spectrometry in 1591 incident colorectal cancer cases (55% women) and 1591 matched controls. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between concentrations of individual lipid metabolites and metabolite patterns with colorectal cancer risk. FINDINGS Of the 97 assayed lipids, 24 were inversely associated (nominally p < 0.05) with colorectal cancer risk. Hydroxysphingomyelin (SM (OH)) C22:2 (ORper doubling 0.60, 95% CI 0.47-0.77) and acylakyl-phosphatidylcholine (PC ae) C34:3 (ORper doubling 0.71, 95% CI 0.59-0.87) remained associated after multiple comparisons correction. These associations were unaltered after excluding the first 5 years of follow-up after blood collection and were consistent according to sex, age at diagnosis, BMI, and colorectal subsite. Two lipid patterns, one including 26 phosphatidylcholines and all sphingolipids, and another 30 phosphatidylcholines, were weakly inversely associated with colorectal cancer. INTERPRETATION Elevated pre-diagnostic circulating levels of SM (OH) C22:2 and PC ae C34:3 and lipid patterns including phosphatidylcholines and sphingolipids were associated with lower colorectal cancer risk. This study may provide insight into potential links between specific lipids and colorectal cancer development. Additional prospective studies are needed to validate the observed associations. FUNDING World Cancer Research Fund (reference: 2013/1002); European Commission (FP7: BBMRI-LPC; reference: 313010).
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Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts.
Ong, KL, Marklund, M, Huang, L, Rye, KA, Hui, N, Pan, XF, Rebholz, CM, Kim, H, Steffen, LM, van Westing, AC, et al
BMJ (Clinical research ed.). 2023;:e072909
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Abstract
OBJECTIVE To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). DESIGN Pooled analysis. DATA SOURCES A consortium of 19 studies from 12 countries identified up to May 2020. STUDY SELECTION Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate. DATA EXTRACTION AND SYNTHESIS Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis. MAIN OUTCOME MEASURES Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m2. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m2 and <75% of baseline rate. RESULTS 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I2=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I2=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I2=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 v <60 years), estimated glomerular filtration rate (60-89 v ≥90 mL/min/1.73 m2), hypertension, diabetes, and coronary heart disease at baseline. CONCLUSIONS Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.
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Metabolic health and cardiometabolic risk clusters: implications for prediction, prevention, and treatment.
Stefan, N, Schulze, MB
The lancet. Diabetes & endocrinology. 2023;(6):426-440
Abstract
Among 20 leading global risk factors for years of life lost in 2040, reference forecasts point to three metabolic risks-high blood pressure, high BMI, and high fasting plasma glucose-as being the top risk variables. Building upon these and other risk factors, the concept of metabolic health is attracting much attention in the scientific community. It focuses on the aggregation of important risk factors, which allows the identification of subphenotypes, such as people with metabolically unhealthy normal weight or metabolically healthy obesity, who strongly differ in their risk of cardiometabolic diseases. Since 2018, studies that used anthropometrics, metabolic characteristics, and genetics in the setting of cluster analyses proposed novel metabolic subphenotypes among patients at high risk (eg, those with diabetes). The crucial point now is whether these subphenotyping strategies are superior to established cardiometabolic risk stratification methods regarding the prediction, prevention, and treatment of cardiometabolic diseases. In this Review, we carefully address this point and conclude, firstly, regarding cardiometabolic risk stratification, in the general population both the concept of metabolic health and the cluster approaches are not superior to established risk prediction models. However, both subphenotyping approaches might be informative to improve the prediction of cardiometabolic risk in subgroups of individuals, such as those in different BMI categories or people with diabetes. Secondly, the applicability of the concepts by treating physicians and communication of the cardiometabolic risk with patients is easiest using the concept of metabolic health. Finally, the approaches to identify cardiometabolic risk clusters in particular have provided some evidence that they could be used to allocate individuals to specific pathophysiological risk groups, but whether this allocation is helpful for prevention and treatment still needs to be determined.
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Ultra-processed foods, adiposity and risk of head and neck cancer and oesophageal adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition study: a mediation analysis.
Morales-Berstein, F, Biessy, C, Viallon, V, Goncalves-Soares, A, Casagrande, C, Hémon, B, Kliemann, N, Cairat, M, Blanco Lopez, J, Al Nahas, A, et al
European journal of nutrition. 2023
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Expert Review
Conflicts of interest:
None
Take Home Message:
UPF intake influences incidence of cancers of the head, neck and oesophagus, this impact appears to be regardless of their impact on adiposity.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
This study evaluated the relationship between consumption of ultra-processed foods and risk of developing cancer of the head and neck (HNC) and oesophagus (OAC), and the role of adiposity in this relationship.
Methods
- Data from the EPIC study including 450111 participants from 10 countries with a mean follow-up duration 14.13 + 3.98 years
- Dietary intakes evaluated using validated questionnaires
- Dietary intakes analysed by firstly identifying ingredients from meals, whether home-made or elsewhere. These components then analysed using NOVA classification of food by extent of processing. NOVA 1 - minimally processed natural foods; NOVA 2 - culinary ingredients e.g. oil, butter, salt, derived from NOVA1 foods with minimal processing; NOVA 3 - industrial products, containing both processed and unprocessed or minimally processed components; NOVA 4 - processed foods not normally used in domestic kitchens, additives intended to enhance taste and/or attractiveness to consumers
- NOVA 3 and 4 foods considered ultra-processed foods (UPF)
- Cancers of the oesophagus, oral cavity, larynx, and pharynx identified from registries, insurance records, and direct follow up
- Participant age, level of education and physical activity were also collected. Height, weight, waist and hip circumference used to calculate BMI and waist to hip ratio (WHR)
- Cox proportional hazards models used to calculate Hazard Ratios (HR. for associations between food intake, cancer incidence and participant characteristics
- Data adjusted for alcohol intake and smoking status.
Results
- 70.8% participants female, mean age at recruitment 51.1 years
- . Mean UPF consumption (g/d) and percentage of total dietary intake varied between countries, from 13.7% (363 g/d) in Spain to 18.6% (520.5 g/d) in the UK
- Male participants had higher mean UPF intake than females, 14.7% versus 13.3% of diet
- Higher UPF intake was associated with increased risk of cancer. For HNC 10% increase in UPF = HR 1.23 (95% CI 1.14-1.34). For OAC HR =1.24 (95% CI = 1.05-1.47
- Greatest effect was seen for cancers of the hypopharynx
- Increased risk was not explained by adiposity: only 5% increased risk for HNC was associated with WHR and 13% increased OAC risk attributable to BMI and WHR.
Conclusion
UPF consumption is associated with increased risks of HNC and OAC, by mechanisms other than increased adiposity.
Clinical practice applications:
- People at risk of HNC or OAC should be made aware of the evidence here of additional risks of consuming UPF
- Although increased adiposity, smoking and consumption of alcohol have some impact on incidence of these cancers, UPF consumption appears to act through some other mechanisms
- Clear definitions of degrees of food processing are provided by this study.
Considerations for future research:
Further areas are worth exploring:
- The impact on UPF intake on the intake of other food groups, for example was UPF intake associated with decreased intake of fruit and vegetables?
- The impact of UPF intake on oral and oesophageal microbiome composition could be considered.
Abstract
PURPOSE To investigate the role of adiposity in the associations between ultra-processed food (UPF) consumption and head and neck cancer (HNC) and oesophageal adenocarcinoma (OAC) in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS Our study included 450,111 EPIC participants. We used Cox regressions to investigate the associations between the consumption of UPFs and HNC and OAC risk. A mediation analysis was performed to assess the role of body mass index (BMI) and waist-to-hip ratio (WHR) in these associations. In sensitivity analyses, we investigated accidental death as a negative control outcome. RESULTS During a mean follow-up of 14.13 ± 3.98 years, 910 and 215 participants developed HNC and OAC, respectively. A 10% g/d higher consumption of UPFs was associated with an increased risk of HNC (hazard ratio [HR] = 1.23, 95% confidence interval [CI] 1.14-1.34) and OAC (HR = 1.24, 95% CI 1.05-1.47). WHR mediated 5% (95% CI 3-10%) of the association between the consumption of UPFs and HNC risk, while BMI and WHR, respectively, mediated 13% (95% CI 6-53%) and 15% (95% CI 8-72%) of the association between the consumption of UPFs and OAC risk. UPF consumption was positively associated with accidental death in the negative control analysis. CONCLUSIONS We reaffirmed that higher UPF consumption is associated with greater risk of HNC and OAC in EPIC. The proportion mediated via adiposity was small. Further research is required to investigate other mechanisms that may be at play (if there is indeed any causal effect of UPF consumption on these cancers).
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A nutritional biomarker score of the Mediterranean diet and incident type 2 diabetes: Integrated analysis of data from the MedLey randomised controlled trial and the EPIC-InterAct case-cohort study.
Sobiecki, JG, Imamura, F, Davis, CR, Sharp, SJ, Koulman, A, Hodgson, JM, Guevara, M, Schulze, MB, Zheng, JS, Agnoli, C, et al
PLoS medicine. 2023;20(4):e1004221
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Plain language summary
Self-reported adherence to the Mediterranean diet (MedDiet) has been associated with a lower incidence of type 2 diabetes (T2D). However, as no biological indicators of whether people are really following the MedDiet have been recorded, it is difficult to definitively ascertain any associations. This post-hoc analysis of a randomised control trial and a cohort study aimed to determine indicative nutritional biomarkers associated with the MedDiet and to see if associations exist with the incidence of T2D. The study formulated a biomarker score based on 29 different nutrients that are in abundance in the MedDiet. This score was then applied to an observational study and showed that as the score went up and therefore adherence to the diet, the incidence of T2D went down and vice versa. Higher adherence to the MedDiet resulted in an 11% decrease in the incidence of T2D. It was concluded that adherence to the MedDiet may help to prevent T2D. This study could be used by healthcare professionals to recommend the commencement of the MedDiet in individuals who are risk of its development.
Abstract
BACKGROUND Self-reported adherence to the Mediterranean diet has been modestly inversely associated with incidence of type 2 diabetes (T2D) in cohort studies. There is uncertainty about the validity and magnitude of this association due to subjective reporting of diet. The association has not been evaluated using an objectively measured biomarker of the Mediterranean diet. METHODS AND FINDINGS We derived a biomarker score based on 5 circulating carotenoids and 24 fatty acids that discriminated between the Mediterranean or habitual diet arms of a parallel design, 6-month partial-feeding randomised controlled trial (RCT) conducted between 2013 and 2014, the MedLey trial (128 participants out of 166 randomised). We applied this biomarker score in an observational study, the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, to assess the association of the score with T2D incidence over an average of 9.7 years of follow-up since the baseline (1991 to 1998). We included 22,202 participants, of whom 9,453 were T2D cases, with relevant biomarkers from an original case-cohort of 27,779 participants sampled from a cohort of 340,234 people. As a secondary measure of the Mediterranean diet, we used a score estimated from dietary-self report. Within the trial, the biomarker score discriminated well between the 2 arms; the cross-validated C-statistic was 0.88 (95% confidence interval (CI) 0.82 to 0.94). The score was inversely associated with incident T2D in EPIC-InterAct: the hazard ratio (HR) per standard deviation of the score was 0.71 (95% CI: 0.65 to 0.77) following adjustment for sociodemographic, lifestyle and medical factors, and adiposity. In comparison, the HR per standard deviation of the self-reported Mediterranean diet was 0.90 (95% CI: 0.86 to 0.95). Assuming the score was causally associated with T2D, higher adherence to the Mediterranean diet in Western European adults by 10 percentiles of the score was estimated to reduce the incidence of T2D by 11% (95% CI: 7% to 14%). The study limitations included potential measurement error in nutritional biomarkers, unclear specificity of the biomarker score to the Mediterranean diet, and possible residual confounding. CONCLUSIONS These findings suggest that objectively assessed adherence to the Mediterranean diet is associated with lower risk of T2D and that even modestly higher adherence may have the potential to reduce the population burden of T2D meaningfully. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000602729 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363860.
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Baseline and lifetime alcohol consumption and risk of skin cancer in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).
Mahamat-Saleh, Y, Al-Rahmoun, M, Severi, G, Ghiasvand, R, Veierod, MB, Caini, S, Palli, D, Botteri, E, Sacerdote, C, Ricceri, F, et al
International journal of cancer. 2023;(3):348-362
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Abstract
Experimental evidence suggests that alcohol induces cutaneous carcinogenesis, yet epidemiological studies on the link between alcohol intake and skin cancer have been inconsistent. The European Prospective Investigation into Cancer and Nutrition (EPIC) is a prospective cohort initiated in 1992 in 10 European countries. Alcohol intake at baseline and average lifetime alcohol intake were assessed using validated country-specific dietary and lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in Cox models. A total of 14 037 skin cancer cases (melanoma: n = 2457; basal-cell carcinoma (BCC): n = 8711; squamous-cell carcinoma (SCC): n = 1928; unknown: n = 941) were identified among 450 112 participants (average follow-up: 15 years). Baseline alcohol intake was positively associated with SCC (>15 vs 0.1-4.9 g/day: HR = 1.44, 95% CI = 1.17-1.77; Ptrend = .001), BCC (HR = 1.12, 95% CI = 1.01-1.23; Ptrend = .04), and melanoma risks in men (HR = 1.17, 95% CI = 0.95-1.44; Ptrend = .17), while associations were more modest in women (SCC: HR = 1.09, 95% CI = 0.90-1.30; Ptrend = .13; BCC: HR = 1.08, 95% CI = 1.00-1.17, Ptrend = .03; melanoma: HR = 0.93, 95% CI = 0.80-1.08, Ptrend = .13). Associations were similar for lifetime alcohol intake, with an attenuated linear trend. Lifetime liquor/spirit intake was positively associated with melanoma (fourth vs first quartile: HR = 1.47, 95% CI = 1.08-1.99; Ptrend = .0009) and BCC risks in men (HR = 1.17, 95% CI = 1.04-1.31; Ptrend = .14). Baseline and lifetime intakes of wine were associated with BCC risk (HR = 1.25 in men; HR = 1.11-1.12; in women). No statistically significant associations were found between beverage types and SCC risk. Intake of beer was not associated with skin cancer risk. Our study suggests positive relationships between alcohol intake and skin cancer risk, which may have important implications for the primary prevention of skin cancer.
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Mediating Role of Lifestyle Behaviors in the Association between Education and Cancer: Results from the European Prospective Investigation into Cancer and Nutrition.
Macciotta, A, Catalano, A, Giraudo, MT, Weiderpass, E, Ferrari, P, Freisling, H, Colorado-Yohar, SM, Santiuste, C, Amiano, P, Heath, AK, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2023;(1):132-140
Abstract
BACKGROUND Many studies have shown that socioeconomic position (SEP) is associated with the incidence of malignant tumors at different sites. This study aims to estimate the association between educational level (as proxy for SEP) and cancer incidence and to understand whether the observed associations might be partially explained by lifestyle behaviors. METHODS The analyses were performed on data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, globally and by sex. We used Cox proportional hazards models together with mediation analysis to disentangle the total effect (TE) of educational level [measured through the Relative Index of Inequality (RII)] on cancer incidence into pure direct (PDE) and total indirect (TIE) effect, unexplained and explained by mediators, respectively. PDE and TIE were then combined to compute the proportions mediated (PM). RESULTS After an average of 14 years of follow-up, 52,422 malignant tumors were ascertained. Low educated participants showed higher risk of developing stomach, lung, kidney (in women), and bladder (in men) cancers, and, conversely, lower risk of melanoma and breast cancer (in post-menopausal women), when compared with more educated participants. Mediation analyses showed that portions of the TE of RII on cancer could be explained by site-specific related lifestyle behaviors for stomach, lung, and breast (in women). CONCLUSIONS Cancer incidence in Europe is determined at least in part by a socioeconomically stratified distribution of risk factors. IMPACT These observational findings support policies to reduce cancer occurrence by altering mediators, such as lifestyle behaviors, particularly focusing on underprivileged strata of the population.
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Circulating amino acid levels and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition and UK Biobank cohorts.
Rothwell, JA, Bešević, J, Dimou, N, Breeur, M, Murphy, N, Jenab, M, Wedekind, R, Viallon, V, Ferrari, P, Achaintre, D, et al
BMC medicine. 2023;(1):80
Abstract
BACKGROUND Amino acid metabolism is dysregulated in colorectal cancer patients; however, it is not clear whether pre-diagnostic levels of amino acids are associated with subsequent risk of colorectal cancer. We investigated circulating levels of amino acids in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts. METHODS Concentrations of 13-21 amino acids were determined in baseline fasting plasma or serum samples in 654 incident colorectal cancer cases and 654 matched controls in EPIC. Amino acids associated with colorectal cancer risk following adjustment for the false discovery rate (FDR) were then tested for associations in the UK Biobank, for which measurements of 9 amino acids were available in 111,323 participants, of which 1221 were incident colorectal cancer cases. RESULTS Histidine levels were inversely associated with colorectal cancer risk in EPIC (odds ratio [OR] 0.80 per standard deviation [SD], 95% confidence interval [CI] 0.69-0.92, FDR P-value=0.03) and in UK Biobank (HR 0.93 per SD, 95% CI 0.87-0.99, P-value=0.03). Glutamine levels were borderline inversely associated with colorectal cancer risk in EPIC (OR 0.85 per SD, 95% CI 0.75-0.97, FDR P-value=0.08) and similarly in UK Biobank (HR 0.95, 95% CI 0.89-1.01, P=0.09) In both cohorts, associations changed only minimally when cases diagnosed within 2 or 5 years of follow-up were excluded. CONCLUSIONS Higher circulating levels of histidine were associated with a lower risk of colorectal cancer in two large prospective cohorts. Further research to ascertain the role of histidine metabolism and potentially that of glutamine in colorectal cancer development is warranted.
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Body mass index and cancer risk among adults with and without cardiometabolic diseases: evidence from the EPIC and UK Biobank prospective cohort studies.
Fontvieille, E, Viallon, V, Recalde, M, Cordova, R, Jansana, A, Peruchet-Noray, L, Lennon, H, Heath, AK, Aune, D, Christakoudi, S, et al
BMC medicine. 2023;(1):418
Abstract
BACKGROUND Whether cancer risk associated with a higher body mass index (BMI), a surrogate measure of adiposity, differs among adults with and without cardiovascular diseases (CVD) and/or type 2 diabetes (T2D) is unclear. The primary aim of this study was to evaluate separate and joint associations of BMI and CVD/T2D with the risk of cancer. METHODS This is an individual participant data meta-analysis of two prospective cohort studies, the UK Biobank (UKB) and the European Prospective Investigation into Cancer and nutrition (EPIC), with a total of 577,343 adults, free of cancer, T2D, and CVD at recruitment. We used Cox proportional hazard regressions to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between BMI and incidence of obesity-related cancer and in turn overall cancer with a multiplicative interaction between BMI and the two cardiometabolic diseases (CMD). HRs and 95% CIs for separate and joint associations for categories of overweight/obesity and CMD status were estimated, and additive interaction was quantified through relative excess risk due to interaction (RERI). RESULTS In the meta-analysis of both cohorts, BMI (per ~ 5 kg/m2) was positively associated with the risk of obesity-related cancer among participants without a CMD (HR: 1.11, 95%CI: 1.07,1.16), among participants with T2D (HR: 1.11, 95% CI: 1.05,1.18), among participants with CVD (HR: 1.17, 95% CI: 1.11,1.24), and suggestively positive among those with both T2D and CVD (HR: 1.09, 95% CI: 0.94,1.25). An additive interaction between obesity (BMI ≥ 30 kg/m2) and CVD with the risk of overall cancer translated into a meta-analytical RERI of 0.28 (95% CI: 0.09-0.47). CONCLUSIONS Irrespective of CMD status, higher BMI increased the risk of obesity-related cancer among European adults. The additive interaction between obesity and CVD suggests that obesity prevention would translate into a greater cancer risk reduction among population groups with CVD than among the general population.
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Replacement of dietary saturated with unsaturated fatty acids is associated with beneficial effects on lipidome metabolites: a secondary analysis of a randomized trial.
Sellem, L, Eichelmann, F, Jackson, KG, Wittenbecher, C, Schulze, MB, Lovegrove, JA
The American journal of clinical nutrition. 2023;(6):1248-1261
Abstract
BACKGROUND The effects of replacing dietary saturated fatty acids (SFAs) with monounsaturated fatty acids (MUFAs) and/or polyunsaturated fatty acids (PUFAs) on the plasma lipidome in relation to the cardiometabolic disease (CMD) risk is poorly understood. OBJECTIVES We aimed to assess the impact of substituting dietary SFAs with unsaturated fatty acids (UFAs) on the plasma lipidome and examine the relationship between lipid metabolites modulated by diet and CMD risk. METHODS Plasma fatty acid (FA) concentrations among 16 lipid classes (within-class FAs) were measured in a subgroup from the Dietary Intervention and VAScular function (DIVAS) parallel randomized controlled trial (n = 113/195), which consisted of three 16-wk diets enriched in SFAs (target SFA:MUFA:n-6PUFA ratio = 17:11:4% total energy [TE]), MUFAs (9:19:4% TE), or a MUFA/PUFA mixture (9:13:10% TE). Similar lipidomics analyses were conducted in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study (specific case/cohorts: n = 775/1886 for type 2 diabetes [T2D], n = 551/1671 for cardiovascular disease [CVD]). Multiple linear regression and multivariable Cox models identified within-class FAs sensitive to replacement of dietary SFA with UFA in DIVAS and their association with CMD risk in EPIC-Potsdam. Elastic-net regression models identified within-class FAs associated with changes in CMD risk markers post-DIVAS interventions. RESULTS DIVAS high-UFA interventions reduced plasma within-class FAs associated with a higher CVD risk in EPIC-Potsdam, especially SFA-containing glycerolipids and sphingolipids (e.g., diacylglycerol (20:0) z-score = -1.08; SE = 0.17; P value < 10-8), whereas they increased those inversely associated with CVD risk. The results on T2D were less clear. Specific sphingolipids and phospholipids were associated with changes in markers of endothelial function and ambulatory blood pressure, whereas higher low-density lipoprotein cholesterol concentrations were characterized by higher plasma glycerolipids containing lauric and stearic acids. CONCLUSIONS These results suggest a mediating role of plasma lipid metabolites in the association between dietary fat and CMD risk. Future research combining interventional and observational findings will further our understanding of the role of dietary fat in CMD etiology. This trial was registered in ClinicalTrials.gov as NCT01478958.