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Abstract Background The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular factors modify the efficacy of dietary or lifestyle interventions to prevent T2D. Methods We searched MEDLINE, Embase, and Cochrane databases for studies reporting on the effect of a lifestyle, dietary pattern, or dietary supplement interventions on the incidence of T2D and reporting the results stratified by any effect modifier. We extracted relevant statistical findings and qualitatively synthesized the evidence for each modifier based on the direction of findings reported in available studies. We used the Diabetes Canada Clinical Practice Scale to assess the certainty of the evidence for a given effect modifier. Results The 81 publications that met our criteria for inclusion are from 33 unique trials. The evidence is low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition. Conclusions We report evidence, albeit low certainty, that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.

BackgroundThe American Heart Association's Life's Essential 8 (LE8) is an updated construct of cardiovascular health (CVH), including blood pressure, lipids, glucose, body mass index, nicotine exposure, diet, physical activity, and sleep health. It is challenging to simultaneously measure all eight metrics at multiple time points in most research and clinical settings, hindering the use of LE8 to assess individuals' overall CVH trajectories over time.Materials and methodsWe obtained data from 5,588 participants in the Nurses' Health Studies (NHS, NHSII) and Health Professionaĺs Follow-up Study (HPFS), and 27,194 participants in the 2005–2016 National Health and Nutrition Examination Survey (NHANES) with all eight metrics available. Individuals' overall cardiovascular health (CVH) was determined by LE8 score (0–100). CVH-related factors that are routinely collected in many settings (i.e., demographics, BMI, smoking, hypertension, hypercholesterolemia, and diabetes) were included as predictors in the base models of LE8 score, and subsequent models further included less frequently measured factors (i.e., physical activity, diet, blood pressure, and sleep health). Gradient boosting decision trees were trained with hyper-parameters tuned by cross-validations.ResultsThe base models trained using NHS, NHSII, and HPFS had validated root mean squared errors (RMSEs) of 8.06 (internal) and 16.72 (external). Models with additional predictors further improved performance. Consistent results were observed in models trained using NHANES. The predicted CVH scores can generate consistent effect estimates in associational studies as the observed CVH scores.ConclusionsCVH-related factors routinely measured in many settings can be used to accurately estimate individuals' overall CVH when LE8 metrics are incomplete.

Summary: Background: Suboptimal diet quality is a key risk factor for premature death. Assuming relatively stable energy intake among individuals, changes in nutrient intakes occur by exchanging different nutrients. Therefore we aimed to examine the association of isocaloric substitution of dietary (macro)nutrients with all-cause mortality using network meta-analysis (NMA). Methods: For this systematic review and NMA of prospective observational studies MEDLINE, Embase, and Scopus were searched from inception to February 13th, 2024. Eligible studies reported substitution analyses for quantity and/or quality of macronutrients, including carbohydrates, proteins, and fatty acids on all-cause mortality. Random-effects NMA were used in order to evaluate the pooled hazard ratios (HR) and 95% confidence intervals (CI) of substituting each included nutrient with another. We assessed risk of bias with the ROBINS-E tool, and the certainty of evidence (CoE) using the Grading of Recommendations Assessment, Development and Evaluations (GRADE) approach. This study is registered with PROSPERO (CRD42023450706). Findings: Thirty-nine studies with 1,737,644 participants, 395,491 deaths, 297 direct comparisons, and seven nutrient-specific networks were included. Moderate CoE was found for an association with lower mortality risk when replacing 5% of energy intake from carbohydrates with polyunsaturated fatty acids (PUFA; HR: 0.90; 95%CI: 0.84, 0.95), n-6 PUFA (0.85; 0.77, 0.94), n-3 PUFA (0.72; 0.59, 0.86), and plant monounsaturated fatty acids (MUFA; 0.90; 0.85, 0.95), and when replacing 5% of energy from saturated fatty acids (SFA) and trans-fatty acids (TFA), with PUFA, MUFA, and plant-MUFA (HRrange: 0.75 to 0.91). A lower mortality risk was additionally found when 5% of animal-MUFA was replaced with plant-MUFA, and when replacing animal protein, and SFA with plant protein (HRrange: 0.81 to 0.87, moderate CoE). Interpretation: Our results provide practical knowledge for public health professionals and can inform upcoming dietary guidelines. The beneficial association of increasing PUFA (both n-3 and n-6) and (plant-) MUFA intake while reducing carbohydrates, SFA and TFA, along with replacing animal protein and animal-MUFA with plant-based sources of protein and fat (MUFA) on the all-cause mortality risk, underscores the importance of plant-based dietary recommendations. Funding: None.

Abstract Background Legume consumption has been linked to a reduced risk of type 2 diabetes (T2D) and cardiovascular disease (CVD), while the potential association between plasma metabolites associated with legume consumption and the risk of cardiometabolic diseases has never been explored. Therefore, we aimed to identify a metabolite signature of legume consumption, and subsequently investigate its potential association with the incidence of T2D and CVD. Methods The current cross-sectional and longitudinal analysis was conducted in 1833 PREDIMED study participants (mean age 67 years, 57.6% women) with available baseline metabolomic data. A subset of these participants with 1-year follow-up metabolomics data (n = 1522) was used for internal validation. Plasma metabolites were assessed through liquid chromatography-tandem mass spectrometry. Cross-sectional associations between 382 different known metabolites and legume consumption were performed using elastic net regression. Associations between the identified metabolite profile and incident T2D and CVD were estimated using multivariable Cox regression models. Results Specific metabolic signatures of legume consumption were identified, these included amino acids, cortisol, and various classes of lipid metabolites including diacylglycerols, triacylglycerols, plasmalogens, sphingomyelins and other metabolites. Among these identified metabolites, 22 were negatively and 18 were positively associated with legume consumption. After adjustment for recognized risk factors and legume consumption, the identified legume metabolite profile was inversely associated with T2D incidence (hazard ratio (HR) per 1 SD: 0.75, 95% CI 0.61–0.94; p = 0.017), but not with CVD incidence risk (1.01, 95% CI 0.86–1.19; p = 0.817) over the follow-up period. Conclusions This study identified a set of 40 metabolites associated with legume consumption and with a reduced risk of T2D development in a Mediterranean population at high risk of cardiovascular disease. Trial registration: ISRCTN35739639.

Abstract Background Olive oil consumption has been inversely associated with the risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, the impact of olive oil consumption on plasma metabolites remains poorly understood. This study aims to identify plasma metabolites related to total and specific types of olive oil consumption, and to assess the prospective associations of the identified multi-metabolite profiles with the risk of T2D and CVD. Methods The discovery population included 1837 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) trial with available metabolomics data at baseline. Olive oil consumption was determined through food-frequency questionnaires (FFQ) and adjusted for total energy. A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation sample. Plasma metabolomics analyses were performed using LC–MS. Cross-sectional associations between 385 known candidate metabolites and olive oil consumption were assessed using elastic net regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite-weighted models and FFQ-derived olive oil consumption in each pair of training–validation data sets within the discovery sample. We further estimated the prospective associations of the identified plasma multi-metabolite profile with incident T2D and CVD using multivariable Cox regression models. Results We identified a metabolomic signature for the consumption of total olive oil (with 74 metabolites), VOO (with 78 metabolites), and COO (with 17 metabolites), including several lipids, acylcarnitines, and amino acids. 10-CV Pearson correlation coefficients between total olive oil consumption derived from FFQs and the multi-metabolite profile were 0.40 (95% CI 0.37, 0.44) and 0.27 (95% CI 0.22, 0.31) for the discovery and validation sample, respectively. We identified several overlapping and distinct metabolites according to the type of olive oil consumed. The baseline metabolite profiles of total and extra virgin olive oil were inversely associated with CVD incidence (HR per 1SD: 0.79; 95% CI 0.67, 0.92 for total olive oil and 0.70; 0.59, 0.83 for extra virgin olive oil) after adjustment for confounders. However, no significant associations were observed between these metabolite profiles and T2D incidence. Conclusions This study reveals a panel of plasma metabolites linked to the consumption of total and specific types of olive oil. The metabolite profiles of total olive oil consumption and extra virgin olive oil were associated with a decreased risk of incident CVD in a high cardiovascular-risk Mediterranean population, though no associations were observed with T2D incidence. Trial registration : The PREDIMED trial was registered at ISRCTN ( http://www.isrctn.com/ , ISRCTN35739639).

Abstract Background A healthy lifestyle (HL) has been inversely related to type 2 diabetes (T2D) and cardiovascular disease (CVD). However, few studies have identified a metabolite profile associated with HL. The present study aims to identify a metabolite profile of a HL score and assess its association with the incidence of T2D and CVD in individuals at high cardiovascular risk. Methods In a subset of 1833 participants (age 55-80y) of the PREDIMED study, we estimated adherence to a HL using a composite score based on the 2018 Word Cancer Research Fund/American Institute for Cancer Research recommendations. Plasma metabolites were analyzed using LC-MS/MS methods at baseline (discovery sample) and 1-year of follow-up (validation sample). Cross-sectional associations between 385 known metabolites and the HL score were assessed using elastic net regression. A 10-cross-validation procedure was used, and correlation coefficients or AUC were assessed between the identified metabolite profiles and the self-reported HL score. We estimated the associations between the identified metabolite profiles and T2D and CVD using multivariable Cox regression models. Results The metabolite profiles that identified HL as a dichotomous or continuous variable included 24 and 58 metabolites, respectively. These are amino acids or derivatives, lipids, and energy intermediates or xenobiotic compounds. After adjustment for potential confounders, baseline metabolite profiles were associated with a lower risk of T2D (hazard ratio [HR] and 95% confidence interval (CI): 0.54, 0.38–0.77 for dichotomous HL, and 0.22, 0.11–0.43 for continuous HL). Similar results were observed with CVD (HR, 95% CI: 0.59, 0.42–0.83 for dichotomous HF and HR, 95%CI: 0.58, 0.31–1.07 for continuous HL). The reduction in the risk of T2D and CVD was maintained or attenuated, respectively, for the 1-year metabolomic profile. Conclusions In an elderly population at high risk of CVD, a set of metabolites was selected as potential metabolites associated with the HL pattern predicting the risk of T2D and, to a lesser extent, CVD. These results support previous findings that some of these metabolites are inversely associated with the risk of T2D and CVD. Trial registration The PREDIMED trial was registered at ISRCTN ( http://www.isrctn.com/ , ISRCTN35739639).

Abstract Experimental studies reported biochemical actions underpinning aging processes and mortality, but the relevant metabolic alterations in humans are not well understood. Here we examine the associations of 243 plasma metabolites with mortality and longevity (attaining age 85 years) in 11,634 US (median follow-up of 22.6 years, with 4288 deaths) and 1878 Spanish participants (median follow-up of 14.5 years, with 525 deaths). We find that, higher levels of N2,N2-dimethylguanosine, pseudouridine, N4-acetylcytidine, 4-acetamidobutanoic acid, N1-acetylspermidine, and lipids with fewer double bonds are associated with increased risk of all-cause mortality and reduced odds of longevity; whereas L-serine and lipids with more double bonds are associated with lower mortality risk and a higher likelihood of longevity. We further develop a multi-metabolite profile score that is associated with higher mortality risk. Our findings suggest that differences in levels of nucleosides, amino acids, and several lipid subclasses can predict mortality. The underlying mechanisms remain to be determined.

Dried fruits contain many bioactive compounds broadly classified as phytochemicals including phenolics, flavonoids, carotenoids, proanthocyanidins, stilbenes, chalcones/dihydrochalcones, and phytoestrogens. These compounds have antioxidant effects that may benefit health. Dried fruits are also a diverse group of foods with varying fibre contents. The evaluation of the biological activity of these bioactive compounds, including their bioaccessibility and bioavailability, may contribute to the understanding of the health effects of dried fruits. Limited evidence suggests that dried fruits (raisins, cranberries, dates, and prunes) affect human gut microbiota composition in a potentially beneficial manner (in terms of effects on Bifidobacteria, Faecalibacterium prausnitzii, Lactobacillus, Ruminococcaceae, Klebsiella spp., and Prevotella spp.). There is little epidemiological evidence about the association of dried fruit consumption with cardiovascular disease incidence and mortality, as well as the risk of type 2 diabetes or obesity. Clinical trial evidence for the effects of dried fruit consumption on cardiovascular risk factors, including glycaemic control, is mixed. Clinical trial evidence suggests prunes might preserve bone mineral density in postmenopausal women. Consumption of dried fruits is associated with higher-quality diets. Studies are needed to increase our understanding of the health effects of dried fruits and the underlying biological mechanisms.

Background Both genetic and lifestyle factors contribute to the risk of type 2 diabetes, but the extent to which there is a synergistic effect of the 2 factors is unclear. The aim of this study was to examine the joint associations of genetic risk and diet quality with incident type 2 diabetes. Methods and findings We analyzed data from 35,759 men and women in the United States participating in the Nurses’ Health Study (NHS) I (1986 to 2016) and II (1991 to 2017) and the Health Professionals Follow-up Study (HPFS; 1986 to 2016) with available genetic data and who did not have diabetes, cardiovascular disease, or cancer at baseline. Genetic risk was characterized using both a global polygenic score capturing overall genetic risk and pathway-specific polygenic scores denoting distinct pathophysiological mechanisms. Diet quality was assessed using the Alternate Healthy Eating Index (AHEI). Cox models were used to calculate hazard ratios (HRs) for type 2 diabetes after adjusting for potential confounders. With over 902,386 person-years of follow-up, 4,433 participants were diagnosed with type 2 diabetes. The relative risk of type 2 diabetes was 1.29 (95% confidence interval [CI] 1.25, 1.32; P < 0.001) per standard deviation (SD) increase in global polygenic score and 1.13 (1.09, 1.17; P < 0.001) per 10-unit decrease in AHEI. Irrespective of genetic risk, low diet quality, as compared to high diet quality, was associated with approximately 30% increased risk of type 2 diabetes (Pinteraction = 0.69). The joint association of low diet quality and increased genetic risk was similar to the sum of the risk associated with each factor alone (Pinteraction = 0.30). Limitations of this study include the self-report of diet information and possible bias resulting from inclusion of highly educated participants with available genetic data. Conclusions These data provide evidence for the independent associations of genetic risk and diet quality with incident type 2 diabetes and suggest that a healthy diet is associated with lower diabetes risk across all levels of genetic risk. In an observational study of 3 cohorts in the United States, Jordi Merino, Marta Guasch-Ferré, Jun Li, and colleagues investigate the individual and combined associations between genetic risk, diet quality, and risk of type 2 diabetes. Author summary Why was this study done? Both genetic and lifestyle factors contribute to individual-level risk of type 2 diabetes. While previous studies have shown that adherence to a healthy lifestyle is associated with reduced risk of type 2 diabetes regardless of genetic risk, the partial characterization of genetic risk and the predominant assessment of interactions on the multiplicative scale might have prevented previous studies from identifying genetic profiles interacting with dietary exposures. Therefore, understanding how genetic risk and diet quality contribute to the development of type 2 diabetes is important to support evidence-based preventive interventions. What did the researchers do and find? In 3 cohort studies involving 35,759 men and women in the US, we used novel polygenic scores for type 2 diabetes to systematically evaluate the presence of additive and multiplicative interactions between genetic risk and diet quality on the development of type 2 diabetes. We found that both low diet quality and increased overall or pathway-specific genetic risk were independently associated with higher risk of type 2 diabetes. We documented that within any genetic risk category, high diet quality, as compared to low diet quality, was associated with a nearly 30% lower risk of type 2 diabetes. Further, we showed that the risk of type 2 diabetes attributed to the combination of increased genetic risk and low diet quality was similar to the sum of the risks associated with each factor alone. What do these findings mean? Results from this study suggest that consuming a healthier diet is associated with a lower risk of type 2 diabetes regardless of genetic risk. Our results underscore the value of genetic risk assessment to identify individuals at increased disease risk and their potential for risk stratification and surveillance. Such knowledge can serve to inform and design future strategies to advance the prevention of type 2 diabetes.

Background Epidemiologic studies on the relationship between avocado intake and long‐term cardiovascular disease (CVD) risk are lacking. Methods and Results This study included 68 786 women from the NHS (Nurses’ Health Study) and 41 701 men from the HPFS (Health Professionals Follow‐up Study; 1986–2016) who were free of cancer, coronary heart disease, and stroke at baseline. Diet was assessed using validated food frequency questionnaires at baseline and then every 4 years. Cox proportional hazards regressions were used to estimate hazard ratios and 95% CIs. A total of 14 274 incident cases of CVD (9185 coronary heart disease events and 5290 strokes) were documented over 30 years of follow‐up. After adjusting for lifestyle and other dietary factors, compared with nonconsumers, those with analysis‐specific higher avocado intake (≥2 servings/week) had a 16% lower risk of CVD (pooled hazard ratio, 0.84; 95% CI, 0.75–0.95) and a 21% lower risk of coronary heart disease (pooled hazard ratio, 0.79; 95% CI, 0.68–0.91). No significant associations were observed for stroke. Per each half serving/day increase in avocado intake, the pooled hazard ratio for CVD was 0.80 (95% CI, 0.71–0.91). Replacing half a serving/day of margarine, butter, egg, yogurt, cheese, or processed meats with the equivalent amount of avocado was associated with a 16% to 22% lower risk of CVD. Conclusions Higher avocado intake was associated with lower risk of CVD and coronary heart disease in 2 large prospective cohorts of US men and women. The replacement of certain fat‐containing foods with avocado could lead to lower risk of CVD.

Although numerous studies have reported the protective effect of nut consumption on cardiovascular risk, evidence for the role of peanuts in maintaining cardiometabolic health is inconclusive. Presented here are the results from the ARISTOTLE study, a parallel randomized controlled trial evaluating the impact of regular peanut intake on anthropometric, biochemical, and clinical measurements. The 63 healthy subjects that completed the study consumed their habitual diet plus either: a) 25 g/day of skin roasted peanuts (SRP, n = 21), b) two tablespoons (32 g)/day of peanut butter (PB, n = 23) or c) two tablespoons (32 g)/day of a control butter based on peanut oil (CB, n = 19) for 6 months. In addition, a meta-analysis of clinical trials, including data from the ARISTOTLE study, was carried out to update the evidence for the effects of consuming peanuts, including high-oleic peanuts, and peanut butter on healthy subjects and those at high cardiometabolic risk. After a systematic search on PubMed, Web of Science, Cochrane Library and Scopus databases up to July 2021, 11 studies were found to meet the eligibility criteria. In the ARISTOTLE study, lower total cholesterol/HDL-cholesterol and LDL-cholesterol/HDL-cholesterol ratios were found in the SRP group compared to the CB group (p = 0.019 and p = 0.008). The meta-analysis of clinical trials revealed that peanut consumption is associated with a decrease in triglycerides (MD: −0.13; 95% CI, −0.20 to −0.07; p < 0.0001) and that healthy consumers had lower total cholesterol and LDL-cholesterol/HDL-cholesterol ratios compared to the control groups (MD: −0.40; 95% CI, −0.71 to −0.09; p = 0.01 and MD: −0.19; 95% CI, −0.36 to −0.01; p = 0.03, respectively). However, individuals at high cardiometabolic risk experienced an increase in body weight after the peanut interventions (MD: 0.97; 95% CI, 0.54 to 1.41; p < 0.0001), although not in body fat or body mass index. According to the dose-response analyses, body weight increased slightly with higher doses of peanuts. In conclusion, a regular consumption of peanuts seems to modulate lipid metabolism, reducing triglyceride blood levels.Systematic Review Registrationhttps://osf.io/jx34y/, identifier: 10.17605/OSF.IO/MK35Y.

Summary: Background: Metabolomics profiles were consistently associated with type 2 diabetes (T2D) risk, but evidence on long-term metabolite changes and T2D incidence is lacking. We examined the associations of 10-year plasma metabolite changes with subsequent T2D risk. Methods: We conducted a nested T2D case-control study (n=244 cases, n=244 matched controls) within the Nurses' Health Study. Repeated metabolomics profiling (170 targeted metabolites) was conducted in participant blood specimens from 1989/1990 and 2000/2001, and T2D occurred between 2002 and 2008. We related 10-year metabolite changes (Δ-values) to subsequent T2D risk using conditional logistic models, adjusting for baseline metabolite levels and baseline levels and concurrent changes of BMI, diet quality, physical activity, and smoking status. Findings: The 10-year changes of thirty-one metabolites were associated with subsequent T2D risk (false discovery rate-adjusted p-values [FDR]

In the present review, we provide a comprehensive narrative overview of the current knowledge on the effects of total and specific types of nut consumption (excluding nut oil) on blood lipids and lipoproteins. We identified a total of 19 systematic reviews and meta-analyses of randomized controlled trials (RCTs) that were available in PubMed from the inception date to November 2022. A consistent beneficial effect of most nuts, namely total nuts and tree nuts, including walnuts, almonds, cashews, peanuts, and pistachios, has been reported across meta-analyses in decreasing total cholesterol (mean difference, MD, −0.09 to −0.28 mmol/L), LDL-cholesterol (MD, −0.09 to −0.26 mmol/L), and triglycerides (MD, −0.05 to −0.17 mmol/L). However, no effects on HDL-cholesterol have been uncovered. Preliminary evidence indicates that adding nuts into the regular diet reduces blood levels of apolipoprotein B and improves HDL function. There is also evidence that nuts dose-dependently improve lipids and lipoproteins. Sex, age, or nut processing are not effect modifiers, while a lower BMI and higher baseline lipid concentrations enhance blood lipid/lipoprotein responses. While research is still emerging, the evidence thus far indicates that nut-enriched diets are associated with a reduced number of total LDL particles and small, dense LDL particles. In conclusion, evidence from clinical trials has shown that the consumption of total and specific nuts improves blood lipid profiles by multiple mechanisms. Future directions in this field should include more lipoprotein particle, apolipoprotein B, and HDL function studies.

Effective prevention and risk prediction are important for peripheral artery disease (PAD) due to its poor prognosis and the huge disease burden it produces. Circulating amino acids (AA) and their metabolites may serve as biomarkers of PAD risk, but they have been scarcely investigated. The objective was to prospectively analyze the associations of baseline levels of plasma AA (and their pathways) with subsequent risk of PAD and the potential effect modification by a nutritional intervention with the Mediterranean diet (MedDiet). A matched case-control study was nested in the PREDIMED trial, in which participants were randomized to three arms: MedDiet with tree nut supplementation group, MedDiet with extra-virgin olive oil (EVOO) supplementation group or control group (low-fat diet). One hundred and sixty-seven PAD cases were matched with 250 controls. Plasma AA was measured with liquid chromatography/mass spectrometry at the Broad Institute. Baseline tryptophan, serine and threonine were inversely associated with PAD (ORfor 1 SD increase = 0.78 (0.61–0.99); 0.67 (0.51–0.86) and 0.75 (0.59–0.95), respectively) in a multivariable-adjusted conditional logistic regression model. The kynurenine/tryptophan ratio was directly associated with PAD (ORfor 1 SD increase = 1.50 (1.14–1.98)). The nutritional intervention with the MedDiet+nuts modified the association between threonine and PAD (p-value interaction = 0.018) compared with the control group. However, subjects allocated to the MedDiet+EVOO group were protected against PAD independently of baseline threonine. Plasma tryptophan, kynurenine/tryptophan ratio, serine and threonine might serve as early biomarkers of future PAD in subjects at a high risk of cardiovascular disease. The MedDiet supplemented with EVOO exerted a protective effect, regardless of baseline levels of threonine.

Abstract Background The pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identification of new predictor biomarkers. Biomarkers potentially modifiable with lifestyle changes deserve a special interest. Our aims were to analyze: (a) The associations of lysine, 2-aminoadipic acid (2-AAA) or pipecolic acid with the risk of T2D or CVD in the PREDIMED trial; (b) the effect of the dietary intervention on 1-year changes in these metabolites, and (c) whether the Mediterranean diet (MedDiet) interventions can modify the effects of these metabolites on CVD or T2D risk. Methods Two unstratified case-cohort studies nested within the PREDIMED trial were used. For CVD analyses, we selected 696 non-cases and 221 incident CVD cases; for T2D, we included 610 non-cases and 243 type 2 diabetes incident cases. Metabolites were quantified using liquid chromatography–tandem mass spectrometry, at baseline and after 1-year of intervention. Results In weighted Cox regression models, we found that baseline lysine (HR+1 SD increase = 1.26; 95% CI 1.06–1.51) and 2-AAA (HR+1 SD increase = 1.28; 95% CI 1.05–1.55) were both associated with a higher risk of T2D, but not with CVD. A significant interaction (p = 0.032) between baseline lysine and T2D on the risk of CVD was observed: subjects with prevalent T2D and high levels of lysine exhibited the highest risk of CVD. The intervention with MedDiet did not have a significant effect on 1-year changes of the metabolites. Conclusions Our results provide an independent prospective replication of the association of 2-AAA with future risk of T2D. We show an association of lysine with subsequent CVD risk, which is apparently diabetes-dependent. No evidence of effects of MedDiet intervention on lysine, 2-AAA or pipecolic acid changes was found. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003

Background Nut consumption has increased in the US but little evidence exists on the association between changes in nut consumption and weight change. We aimed to evaluate the association between changes in total consumption of nuts and intakes of different nuts (including peanuts) and long-term weight change, in three independent cohort studies.Methods and findings Data collected in three prospective, longitudinal cohorts among health professionals in the US were analysed. We included 27 521 men (Health Professionals Follow-up Study, 1986 to 2010), 61 680 women (Nurses’ Health Study, 1986 to 2010), and 55 684 younger women (Nurses’ Health Study II, 1991 to 2011) who were free of chronic disease at baseline in the analyses. We investigated the association between changes in nut consumption over 4-year intervals and concurrent weight change over 20–24 years of follow-up using multivariate linear models with an unstructured correlation matrix to account for within-individual repeated measures. 21 322 individuals attained a body mass index classification of obesity (BMI ≥30 kg/m2) at the end of follow-up.Average weight gain across the three cohorts was 0.32 kg each year. Increases in nut consumption, per 0.5 servings/day (14 g), was significantly associated with less weight gain per 4-year interval (p

Background We aim to evaluate the association of within‐individual changes in consumption of total and specific types of nuts and the subsequent risk of incident cardiovascular disease (CVD) in US men and women. Methods and Results We included 34 103 men from the HPFS (Health Professionals Follow‐Up Study) (1986–2012), 77 815 women from the NHS (Nurses’ Health Study) (1986–2012), and 80 737 women from the NHS II (1991–2013). We assessed nut consumption every 4 years using validated food frequency questionnaires. We used multivariable Cox proportional hazards regression models to examine the association between 4‐year changes in nut consumption and risk of confirmed CVD end points in the subsequent 4 years. Per 0.5 serving/day increase in total nut consumption was associated with lower risk of CVD (relative risk [RR], 0.92; 95% CI, 0.86–0.98), coronary heart disease (RR, 0.94; 95% CI, 0.89–0.99), and stroke (RR, 0.89; 95% CI, 0.83–0.95). Compared with individuals who remained nonconsumers in a 4‐year interval, those who had higher consumption of total nuts (≥0.5 servings/day) had a lower risk of CVD (RR, 0.75; 95% CI, 0.67–0.84), coronary heart disease (RR, 0.80; 95% CI, 0.69–0.93), and stroke (RR, 0.68; 95% CI, 0.57–0.82) in next 4 years. Individuals who decreased nut consumption by ≥0.50 servings/day had a higher risk of developing CVD (RR, 1.14; 95% CI, 0.99–1.32), coronary heart disease (RR, 1.06; 95% CI, 0.88–1.28), and stroke (RR, 1.28; 95% CI, 1.02–1.60) when compared with those who maintained their nut consumption. Conclusions Increasing total consumption of nuts and intake of individual types of nuts (eg, walnuts, other tree nuts, and peanuts) was associated with a subsequent lower risk of CVD. These data support the role of nut intake in the primary prevention of CVD. Registration URL: http://www.clini​caltr​ials.gov. Unique identifiers: NCT00005152 and NCT00005182.

Walnut consumption is associated with health benefits. We aimed to (1) examine the association between walnut consumption and mortality and (2) estimate life expectancy in relation to walnut consumption in U.S. adults. We included 67,014 women of the Nurses’ Health Study (1998–2018) and 26,326 men of the Health Professionals Follow-up Study (1998–2018) who were free of cancer, heart disease, and stroke at baseline. We used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During up to 20 years of follow-up, we documented 30,263 deaths. The hazard ratios for total mortality across categories of walnut intake (servings/week), as compared to non-consumers, were 0.95 (95% confidence interval (CI), 0.91, 0.98) for =5 servings/week (p for trend non-consumers. Higher walnut consumption was associated with a lower risk of total and CVD mortality and a greater gained life expectancy among U.S. elder adults.

The increased prevalence of atrial fibrillation (AF) and heart failure (HF) highlights the need to better understand the mechanisms underlying these cardiovascular diseases (CVDs). In the present study, we aimed to evaluate the association between glycolysis-related metabolites and the risk of AF and HF in a Mediterranean population at high risk of CVD. We used two case–control studies nested within the PREDIMED trial. A total of 512 incident AF cases matched to 734 controls, and 334 incident HF cases matched to 508 controls, were included. Plasma metabolites were quantified by using hydrophilic interaction liquid chromatography coupled with high-resolution negative ion mode MS detection. Conditional logistic regression analyses were performed. The results showed no association between baseline plasma glycolysis intermediates and other related metabolites with AF. Only phosphoglycerate was associated with a higher risk of HF (OR for 1 SD increase: 1.28; 95% CI: 1.06, 1.53). The present findings do not support a role of the glycolysis pathway in the pathogenesis of AF. However, the increased risk of HF associated with phosphoglycerate requires further studies.

There is little information on the dietary modulation of thrombosis-related risk factors such as platelet count. We aimed to assess the effects of Mediterranean diet (MedDiet) on platelet count and related outcomes in an older population at high cardiovascular risk. In participants of the PREDIMED (PREvención con DIeta MEDiterránea) study, we assessed whether an intervention with a MedDiet enriched with extra-virgin olive oil or nuts, relative to a low-fat control diet, modulated platelet count (n = 4189), the risk of developing thrombocytosis and thrombocytopenia (n = 3086), and the association between these alterations and all-cause mortality (median follow-up time: 3.0 years). Although platelet count increased over time (+0.98·109 units/L·year [95% confidence interval: 0.12; 1.84]), MedDiet interventions moderated this increase, particularly in individuals with near-high baseline count (both MedDiets combined: −3.20·109 units/L·year [−5.81; −0.59]). Thrombocytopenia incidence was lower in the MedDiet interventions (incidence rates: 2.23% in control diet, 0.91% in MedDiets combined; hazard ratio: 0.44 [0.23; 0.83]). Finally, thrombocytopenia was associated with a higher risk of all-cause mortality (hazard ratio: 4.71 [2.69; 8.24]), but this relationship was attenuated in those allocated to MedDiet (p-interaction = 0.018). In brief, MedDiet maintained platelet counts within a healthy range and attenuated platelet-related mortality in older adults at high cardiovascular risk.

BackgroundThe relationship between plasma concentrations of betaine and choline metabolism and major cardiovascular disease (CVD) end points remains unclear. We have evaluated the association between metabolites from the choline pathway and risk of incident CVD and the potential modifying effect of Mediterranean diet interventions. Methods and ResultsWe designed a case‐cohort study nested within the PREDIMED (Prevention With Mediterranean Diet) trial, including 229 incident CVD cases and 751 randomly selected participants at baseline, followed up for 4.8 years. We used liquid chromatography–tandem mass spectrometry to measure, at baseline and at 1 year of follow‐up, plasma concentrations of 5 metabolites in the choline pathway: trimethylamine N‐oxide, betaine, choline, phosphocholine, and α‐glycerophosphocholine. We have calculated a choline metabolite score using a weighted sum of these 5 metabolites. We used weighted Cox regression models to estimate CVD risk. The multivariable hazard ratios (95% confidence intervals) per 1‐SD increase in choline and α‐glycerophosphocholine metabolites were 1.24 (1.05–1.46) and 1.24 (1.03–1.50), respectively. The baseline betaine/choline ratio was inversely associated with CVD. The baseline choline metabolite score was associated with a 2.21‐fold higher risk of CVD across extreme quartiles (95% confidence interval, 1.36–3.59; P

Few studies have examined the association of a wide range of metabolites with total and subtypes of coffee consumption. The aim of this study was to investigate associations of plasma metabolites with total, caffeinated, and decaffeinated coffee consumption. We also assessed the ability of metabolites to discriminate between coffee consumption categories. This is a cross-sectional analysis of 1664 participants from the PREDIMED study. Metabolites were semiquantitatively profiled using a multiplatform approach. Consumption of total coffee, caffeinated coffee and decaffeinated coffee was assessed by using a validated food frequency questionnaire. We assessed associations between 387 metabolite levels with total, caffeinated, or decaffeinated coffee consumption (≥50 mL coffee/day) using elastic net regression analysis. Ten-fold cross-validation analyses were used to estimate the discriminative accuracy of metabolites for total and subtypes of coffee. We identified different sets of metabolites associated with total coffee, caffeinated and decaffeinated coffee consumption. These metabolites consisted of lipid species (e.g., sphingomyelin, phosphatidylethanolamine, and phosphatidylcholine) or were derived from glycolysis (alpha-glycerophosphate) and polyphenol metabolism (hippurate). Other metabolites included caffeine, 5-acetylamino-6-amino-3-methyluracil, cotinine, kynurenic acid, glycocholate, lactate, and allantoin. The area under the curve (AUC) was 0.60 (95% CI 0.56−0.64), 0.78 (95% CI 0.75−0.81) and 0.52 (95% CI 0.49−0.55), in the multimetabolite model, for total, caffeinated, and decaffeinated coffee consumption, respectively. Our comprehensive metabolic analysis did not result in a new, reliable potential set of metabolites for coffee consumption.

BackgroundEpidemiological evidence suggests a cardioprotective role of α‐linolenic acid (ALA), a plant‐derived ω‐3 fatty acid. It is unclear whether ALA is beneficial in a background of high marine ω‐3 fatty acids (long‐chain n‐3 polyunsaturated fatty acids) intake. In persons at high cardiovascular risk from Spain, a country in which fish consumption is customarily high, we investigated whether meeting the International Society for the Study of Fatty Acids and Lipids recommendation for dietary ALA (0.7% of total energy) at baseline was related to all‐cause and cardiovascular disease mortality. We also examined the effect of meeting the society's recommendation for long‐chain n‐3 polyunsaturated fatty acids (≥500 mg/day). Methods and ResultsWe longitudinally evaluated 7202 participants in the PREvención con DIeta MEDiterránea (PREDIMED) trial. Multivariable‐adjusted Cox regression models were fitted to estimate hazard ratios. ALA intake correlated to walnut consumption (r=0.94). During a 5.9‐y follow‐up, 431 deaths occurred (104 cardiovascular disease, 55 coronary heart disease, 32 sudden cardiac death, 25 stroke). The hazard ratios for meeting ALA recommendation (n=1615, 22.4%) were 0.72 (95% CI 0.56–0.92) for all‐cause mortality and 0.95 (95% CI 0.58–1.57) for fatal cardiovascular disease. The hazard ratios for meeting the recommendation for long‐chain n‐3 polyunsaturated fatty acids (n=5452, 75.7%) were 0.84 (95% CI 0.67–1.05) for all‐cause mortality, 0.61 (95% CI 0.39–0.96) for fatal cardiovascular disease, 0.54 (95% CI 0.29–0.99) for fatal coronary heart disease, and 0.49 (95% CI 0.22–1.01) for sudden cardiac death. The highest reduction in all‐cause mortality occurred in participants meeting both recommendations (hazard ratio 0.63 [95% CI 0.45–0.87]). ConclusionsIn participants without prior cardiovascular disease and high fish consumption, dietary ALA, supplied mainly by walnuts and olive oil, relates inversely to all‐cause mortality, whereas protection from cardiac mortality is limited to fish‐derived long‐chain n‐3 polyunsaturated fatty acids. Clinical Trial RegistrationURL: http://www.Controlled-trials.com/. Unique identifier: ISRCTN35739639.

Magnesium (Mg) is an essential dietary element for humans involved in key biological processes. A growing body of evidence from epidemiological studies, randomized controlled trials (RCTs) and meta-analyses have indicated inverse associations between Mg intake and cardiovascular diseases (CVD). The present review aims to summarize recent scientific evidence on the topic, with a focus on data from epidemiological studies assessing the associations between Mg intake and major cardiovascular (CV) risk factors and CVD. We also aimed to review current literature on circulating Mg and CVD, as well as potential biological processes underlying these observations. We concluded that high Mg intake is associated with lower risk of major CV risk factors (mainly metabolic syndrome, diabetes and hypertension), stroke and total CVD. Higher levels of circulating Mg are associated with lower risk of CVD, mainly ischemic heart disease and coronary heart disease. Further, RCTs and prospective studies would help to clarify whether Mg intake and Mg circulating levels may also protect against other CVDs and CVD death.

IntroductionProspective studies have consistently suggested that nut consumption is inversely related to fatal and non-fatal coronary heart disease. Limited data are available on the epidemiological associations between nut intake and cardiometabolic risk factors.ObjectiveTo evaluate associations between frequency of nut consumption and prevalence of cardiometabolic risk factors [obesity, metabolic syndrome (MetS), type-2 diabetes, hypertension, and dyslipidemia] in a Mediterranean population at high cardiovascular risk.Materials and methodsCross-sectional study of 7,210 men and women (mean age, 67 y) recruited into the PREDIMED study. MetS was defined by the harmonized ATPIII and IDF criteria. Diabetes and hypertension were assessed by clinical diagnosis and dyslipidemia (high triglycerides, low HDL-cholesterol, and hypercholesterolemia) by lipid analyses. Nut consumption was assessed using a validated food frequency questionnaire and categorized as 3 servings/wk. Control of confounding was done with multivariate logistic regression.ResultsCompared to participants consuming 3 servings/wk had lower adjusted odds ratios (OR) for obesity (0.61, 95% confidence interval 0.54 to 0.68; P-trend ConclusionsNut consumption was inversely associated with the prevalence of general obesity, central obesity, MetS, and diabetes in subjects at high cardiovascular risk.

IntroductionSeveral anthropometric measurements have been associated with cardiovascular disease, type-2 diabetes mellitus and other cardiovascular risk conditions, such as hypertension or metabolic syndrome. Waist-to-height-ratio has been proposed as a useful tool for assessing abdominal obesity, correcting other measurements for the height of the individual. We compared the ability of several anthropometric measurements to predict the presence of type-2 diabetes, hyperglycemia, hypertension, atherogenic dyslipidemia or metabolic syndrome.Materials and methodsIn our cross-sectional analyses we included 7447 Spanish individuals at high cardiovascular risk, men aged 55-80 years and women aged 60-80 years, from the PREDIMED study. Logistic regression models were fitted to evaluate the odds ratio of presenting each cardiovascular risk factor according to various anthropometric measures. The areas under the receiver-operating characteristic curve (AUC) were used to compare the predictive ability of these measurements.ResultsIn this relatively homogeneous cohort with 48.6% of type-2 diabetic individuals, the great majority of the studied anthropometric parameters were significantly and positively associated with the cardiovascular risk factors. No association was found between BMI and body weight and diabetes mellitus. The AUCs for the waist-to-height ratio and waist circumference were significantly higher than the AUCs for BMI or weight for type-2 diabetes, hyperglycemia, atherogenic dyslipidemia and metabolic syndrome. Conversely, BMI was the strongest predictor of hypertension.ConclusionsWe concluded that measures of abdominal obesity showed higher discriminative ability for diabetes mellitus, high fasting plasma glucose, atherogenic dyslipidemia and metabolic syndrome than BMI or weight in a large cohort of elderly Mediterranean individuals at high cardiovascular risk. No significant differences were found between the predictive abilities of waist-to-height ratio and waist circumference on the metabolic disease.

INTRODUCTION: To develop and test a diabetes risk score to predict incident diabetes in an elderly Spanish Mediterranean population at high cardiovascular risk. MATERIALS AND METHODS: A diabetes risk score was derived from a subset of 1381 nondiabetic individuals from three centres of the PREDIMED study (derivation sample). Multivariate Cox regression model ß-coefficients were used to weigh each risk factor. PREDIMED-personal Score included body-mass-index, smoking status, family history of type 2 diabetes, alcohol consumption and hypertension as categorical variables; PREDIMED-clinical Score included also high blood glucose. We tested the predictive capability of these scores in the DE-PLAN-CAT cohort (validation sample). The discrimination of Finnish Diabetes Risk Score (FINDRISC), German Diabetes Risk Score (GDRS) and our scores was assessed with the area under curve (AUC). RESULTS: The PREDIMED-clinical Score varied from 0 to 14 points. In the subset of the PREDIMED study, 155 individuals developed diabetes during the 4.75-years follow-up. The PREDIMED-clinical score at a cutoff of ≥6 had sensitivity of 72.2%, and specificity of 72.5%, whereas AUC was 0.78. The AUC of the PREDIMED-clinical Score was 0.66 in the validation sample (sensitivity = 85.4%; specificity = 26.6%), and was significantly higher than the FINDRISC and the GDRS in both the derivation and validation samples. DISCUSSION: We identified classical risk factors for diabetes and developed the PREDIMED-clinical Score to determine those individuals at high risk of developing diabetes in elderly individuals at high cardiovascular risk. The predictive capability of the PREDIMED-clinical Score was significantly higher than the FINDRISC and GDRS, and also used fewer items in the questionnaire.