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Introduction:Previous studies have reported inverse associations of circulating and tissue levels of pentadecanoic acid (15:0), heptadecanoic acid (17:0) and trans-palmitoleic acid (trans16:1n-7), which have been proposed as potential biomarkers of dairy fat intake, with risk of type-2 diabetes and certain cardiovascular outcomes.Hypothesis:We assessed the hypothesis that circulating and tissue levels of 15:0, 17:0, trans16:1n-7 are inversely associated with risk of incident coronary heart disease (CHD) and stroke in a global consortium of prospective studies.Methods:We used data from 15 prospective cohorts in the Fatty Acids and Outcomes Research Consortium. We included adults (age≥18 years) who were free of cardiovascular diseases and had blood or adipose tissue measurements of 15:0, 17:0 or trans16:1n-7. We used a harmonized analysis protocol with each exposure standardized to the interquintile range (IQR): difference between the 10thand 90thpercentiles of each fatty acid to conduct new individual participant-level analyses. We harmonized covariate definitions across studies to include demographic, lifestyle and health variables, and levels of other fatty acids associated with CHD or stroke. We used inverse-variance meta-analysis to calculate the pooled relative risks (RR) and 95% confidence intervals (CI) for each outcome. We also calculated Spearman correlation coefficients between levels of each fatty acid exposure and potential dietary determinants of their levels (intakes of total, high-fat and low-fat dairy, meat from ruminant animals, fish and dietary fiber) among 6 studies with dietary data.Results and Conclusions:Among 34,187 participants, 5,790 incident CHD and 3,098 stroke cases were documented during a maximum follow-up of 23.3 years. We did not observe significant associations of any of the fatty acid biomarkers with risk of CHD or stroke. The pooled multivariate RR and 95% CI of CHD per IQR were 0.97 (0.92, 1.02) for 15:0, 0.97 (0.92, 1.02) for 17:0, 1.11 (0.97, 1.26) for trans16:1n-7, and 0.98 (0.92, 1.04) for the sum of the fatty acids. The respective RR and 95% of stroke were 1.01 (0.93, 1.09) for 15:0, 0.91 (0.81, 1.03) for 17:0, 0.99 (0.83, 1.18) for trans16:1n-7, and 0.93 (0.85, 1.04) for the summed fatty acids. Additionally, we did not observe significant heterogeneity by age, sex, race/ethnicity, world region, baseline hypertension status or lipid compartment. Circulating and tissue levels of 15:0, 17:0 and trans16:1n-7 were weakly correlated with intakes of total or high-fat dairy (Spearman correlations [r= 0.05 to 0.37]) but were not correlated with intakes of low-fat dairy, ruminant meat, fish or dietary fiber [r= -0.08 to 0.09]. In conclusion, circulating and tissue levels of 15:0, 17:0, trans16:1n-7 were not associated with risk of CHD or stroke. Our study suggests a limited role for these fatty acids in the etiology of cardiovascular disease.

Background:Individuals with type 2 diabetes (T2D) are at elevated risk of developing peripheral artery disease (PAD). Whether healthy lifestyle can reduce this risk, particularly in individuals genetically predisposed to PAD, is unknown.Aims:To evaluate the association between modifiable lifestyle factors with incident PAD among individuals with T2D, both overall and stratified by genetic risk of PAD.Methods:We included 19,368 individuals with T2D from the UK Biobank, who were free of PAD and cardiovascular disease. We defined a low-risk lifestyle score with 1 point assigned for each of the following: non-current smoking, regular physical activity, adhering to a high-quality diet, moderate alcohol consumption, maintaining a normal waist-hip ratio, sleeping 7-8 hours/day. A polygenic risk score (PRS) including 19 single nucleotide polymorphisms was constructed. Multivariable-adjusted Cox models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI).Results:After a median 7.6 years of follow-up, 325 incident cases of PAD were documented. There was an inverse association between the low-risk lifestyle score and incident PAD, with HR (95%CI) of 0.73 (0.54, 1.03), 0.43 (0.30, 0.60), and 0.42 (0.30, 0.60) for 2, 3, and ≥4 compared with ≤1. The PRS was associated with an increased risk of PAD, with HR (95%CI) of 1.16 (1.03, 1.31) per-SD increment. A more favorable lifestyle was able to partially mitigate the risk of increased genetic susceptibility to PAD (Figure 1). In mediation analysis, 42.4% of the association could be attributable to risk factors including inflammation, atherogenic lipoproteins, and impaired hepatic/renal function.Conclusion:A combined set of modifiable lifestyle factors was associated with a substantially lower risk of incident PAD among individuals with T2D and may be able to partially mitigate an underlying genetic predisposition for PAD. Our findings highlight the importance of improving adherence to these factors in the primary prevention of PAD among individuals with T2D.

Introduction:Incidence of heart failure (HF) is increased among individuals living with human immunodeficiency virus (HIV). Whether HIV adversely affects hospitalization and mortality rates among patients with diagnosed HF has not been systematically evaluated.Hypothesis:We hypothesized that HIV infection would increase the risk of hospitalization and all-cause mortality rates in patients with HF, independent of established risk factors.Methods:We performed a systematic search of PubMed, EMBASE, Cochrane Library and Web of Science through March 7th, 2021 for cohort studies conducted in adult patients (age≥18 years) with diagnosed HF and ascertainment of HIV infection at baseline. Outcomes assessed include all-cause mortality, HF-associated hospitalization, and all-cause hospitalization. All studies included multivariable adjustments for demographics, cardiovascular risk factors, and comorbidities. Pooled hazard ratio (HR) and 95% confidence intervals (CI) were calculated using a random-effects model.Results:We identified 7 studies consisting of 10,363 HF patients living with HIV and 48,933 HIV negative HF controls. HF patients with HIV had a higher risk of all-cause mortality compared to HIV-negative HF patients, HR (95% CI): 1.20 (1.14, 1.25), I2=0%. Similarly, HIV infection was associated with increased risks of both HF-associated hospitalization and all-cause hospitalization, with HR (95% CI) of 1.31 (1.03, 1.65) and 1.27 (1.12, 1.44), respectively; though significant heterogeneity was observed for both of these outcomes, I2=80% and 62%, respectively.Conclusions:HIV infection was independently associated with increased risk of all-cause mortality and both HF-associated and all-cause hospitalizations among individuals with HF. Our data may have important implications for HF management in this high-risk population.

Introduction:Insulin resistance is central to the development of type 2 diabetes (T2D). Association between specific biomarkers of glucose-insulin homeostasis and T2D have been inconsistent. Whether vitamin D or omega-3 fatty acids (n-3 FA) can modify these associations is also unclear.Hypothesis:We hypothesized that higher insulin, C-peptide, insulin resistance score (IRS), and HbA1c are each associated with higher T2D risk, and that these associations would be attenuated among participants who received vitamin D or n-3 FA.Methods:VITAL Diabetes (NCT01633177) was a pre-specified ancillary 2x2 factorial study in the VITAL RCT to assess whether vitamin D (cholecalciferol, 2000 IU/d) or n-3 FA (EPA + DHA, 1 g/d) could prevent T2D. Subjects without baseline reported T2D and with HbA1c <6.5% were included. Incident cases were matched 1:1 on age and sex to healthy controls (N=359 pairs). Conditional logistic regression models with adjustment for demographics, risk factors including BMI, and randomized treatment were used to estimate the adjusted odds ratio (aOR) and 95% CI between baseline measurements of insulin, C-peptide, IRS (Insulinх0.0265+C-peptideх0.00511+Creatinineх-3.2641), HbA1c, and T2D. Interaction was tested between each biomarker and treatment groups (placebo vs vitamin D or n-3 FA).Results:Mean age of participants was 66 years, approximately 45% were female, and 16% were African American. Each of the glucose-insulin homeostasis biomarkers was associated with T2D risk (Table 1), aOR (95% CI) per SD increment, insulin: 1.46 (1.10, 1.94), C-peptide: 1.72 (1.28, 2.31), IRS: 1.59 (1.26, 2.01), and HbA1c: 80.43 (25.90, 249.77). Biomarker associations did not differ by randomized treatment (Pinteraction>0.05).Conclusions:In VITAL Diabetes, insulin, C-peptide, IRS, and HbA1c were each associated with an increased risk of T2D, independent of other risk factors. Randomization to either vitamin D or n-3 FA did not modify these associations.

Introduction:Dysglycemia and insulin resistance increase cardiovascular disease (CVD) risk. Associations between specific glucose-insulin biomarkers and CVD have been inconsistent.Hypothesis:We hypothesized that higher insulin, C-peptide, insulin resistance score (IRS), and HbA1c are associated with incident CVD and coronary heart disease (CHD) events and that both vitamin D and omega-3 fatty acids (n-3 FA) would improve these biomarkers and attenuate their risks with CVD.Methods:VITAL (NCT01169259) was a 2x2 factorial design RCT testing vitamin D (cholecalciferol, 2000 IU/d) and n-3 FA (EPA+DHA, 1 g/d) for the primary prevention of CVD. Incident CVD cases [non-fatal myocardial infarction (MI), non-fatal stroke, or CV death] were matched 1:1 on age and sex to healthy controls (n=715 CVD pairs including 423 CHD [MI, revascularization, CHD death] pairs). Conditional logistic regression adjusting for demographics, CV risk factors, and randomized treatment was used to assess the adjusted odds ratio (aOR) and 95% CI between baseline levels of insulin, C-peptide, IRS (Insulinх0.0265+C-peptideх0.00511+Creatinineх-3.2641), and HbA1c with risk of CVD and CHD events. In control participants, we examined the randomized effects of vitamin D or n-3 FA on changes in these biomarkers at 1- or 2-years follow-up.Results:Mean age of participants was 71 years, approximately 42% were female, and 12% were African American. Baseline insulin, C-peptide, and IRS were not associated with CVD (Figure 1). HbA1c was associated with CVD risk, aOR (95% CI) per SD increment, 1.17 (1.01, 1.38). Of the 4 biomarkers, only IRS was associated with CHD risk, aOR (95% CI): 1.22 (1.01, 1.46). Randomization to vitamin D or n-3 FA did not modify levels of these biomarkers or their associations.Conclusions:HbA1c was significantly associated with CVD risk, whereas IRS was associated with CHD risk. Neither vitamin D nor n-3 FA appreciably modified these biomarker levels or their risk associations.

Background:Women with a history of gestational diabetes mellitus (GDM) are at increased risk for cardiovascular disease (CVD). Whether healthy lifestyle practices can mitigate this risk is unclear.Aims:To prospectively assess associations of healthy lifestyle factors with CVD risk in women with a history of GDM.Methods:We included 4,372 women from the Nurses’ Health Study II with a prior clinician diagnosis of GDM who were free of cancer or CVD at the time of the index pregnancy. Healthy lifestyle factors, which were updated every 2-4 years, included non-current smoking, body mass index<25 kg/m2, regular physical activity (>500 MET-min/week), high-quality diet (above median on the Alternative Healthy Eating Index), and moderate alcohol consumption (>0-15 g/day). A composite outcome of CVD was defined as the combination of nonfatal/fatal myocardial infarction (MI), stroke, angiographically confirmed angina, and coronary artery bypass surgery or angioplasty/stenting. Multivariate-adjusted Cox models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI).Results:During a median 28 years of follow-up, 179 incident CVD events were ascertained. Compared to women with 0 or 1 healthy lifestyle factor, HR (95% CI) for risk of CVD among those who had 2, 3, and ≥4 factors were 1.02 (0.68, 1.53), 0.45 (0.28, 0.74), and 0.32 (0.18, 0.60), respectively (Ptrend< 0.001) (Table 1). Similar results were observed for clinical CVD events (nonfatal/fatal MI or stroke) and total MI. When modeled continuously, each additional healthy lifestyle factor was associated with a lower risk of the composite outcome, HR (95% CI): 0.67 (0.57, 0.80); clinical CVD, HR (95% CI): 0.74 (0.58, 0.94); and MI, HR (95% CI): 0.61 (0.43, 0.86). We estimated that 62.5% (95% CI: 34.9%, 79.0%) of the CVD risk in this population was potentially avoidable with adherence to ≥4 healthy lifestyle factors.Conclusion:Greater adherence to healthy lifestyle factors was associated with a significant reduction in CVD risk in women with a history of GDM.

Background:Biomarker levels of very long-chain saturated fatty acids (VLCSFAs) have been found to be favorably associated with cardiovascular risk factors including lower risk of diabetes and reduced triglycerides. Few studies have examined the association between VLCSFAs and coronary heart disease (CHD).Aims:To assess the association of circulating arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) with incident total, fatal, and nonfatal CHD.Methods:We used data from the Fatty Acids and Outcomes Research Consortium consisting of 15 prospective cohorts worldwide which included adults (age≥18 years) who were free of cardiovascular disease and had blood measurements of 20:0, 22:0, and 24:0 at baseline. A study protocol with standardized definitions of exposures, disease outcomes, and covariates was developed, for which each cohort conducted individual participant-level analysis. Cohort-specific associations were pooled using inverse variance-weighted meta-analysis to calculate the overall relative risk (RR) per interquintile range (difference between the 90thand 10thpercentiles) and 95% confidence interval (CI).Results:Among 33,083 participants, 6,165 cases of total CHD were ascertained. The overall pooled RR and 95% CI were 0.96 (0.89, 1.02) for 20:0, 1.01 (0.92, 1.11) for 22:0, 0.94 (0.86, 1.02) for 24:0, and 0.96 (0.89, 1.04) for 20:0 + 22:0 + 24:0 (Figure 1). However, we noted heterogeneity by lipid compartments, with significant inverse associations for higher 22:0 [0.77 (0.62, 0.96)], 24:0 [0.61 (0.49, 0.77)], and 20:0 + 22:0 + 24:0 [0.73 (0.60, 0.89)] in the total plasma/serum compartment but not in the phospholipid compartment. Similar associations were observed for fatal and nonfatal CHD and when using a random-effects model.Conclusion:Higher circulating VLCSFAs were not associated with total CHD in a global consortium of prospective studies. The finding of an inverse association with total CHD for VLCSFAs in the total plasma/serum compartment warrants further research.

Background:Existing evidence on the relationship between intakes of monounsaturated fatty acids (MUFAs) and risk of developing type 2 diabetes (T2D) is conflicting. Few studies have examined whether MUFAs from plant or animal sources exhibit differential associations with T2D.Aims:To examine the association of intake of total, plant-based (MUFA-Ps), and animal-based MUFAs (MUFA-As) with T2D risk.Methods:We used data from three prospective cohorts which included 54,518 women in Nurses’ Health Study (1990-2012), 88,613 women in Nurses’ Health Study II (1991-2013), and 29,520 men in Health Professionals Follow-up Study (1990-2012). Using validated food-frequency questionnaires and food composition tables, we calculated the average MUFA-Ps and MUFA-As intake in every 4-year period and modeled their association with T2D using Cox regression models.Results:During 3,682,622 person-years of follow-up, we documented 13,077 incident cases of T2D. After multivariate adjustment, total MUFA intake was not associated with risk of T2D. In contrast, MUFA-Ps were associated with a lower risk of T2D, whereas MUFA-As were associated with a higher risk. In iso-caloric substitution analyses, the pooled hazard ratios (HRs) and 95% confidence intervals (CI) were 0.99 (0.88, 1.12; P=0.89) for saturated fat (SFAs, 5% of energy), 0.91 (0.85, 0.98; P=0.01) for refined carbohydrates (5% of energy), and 0.87 (0.80, 0.94; P=0.0006) for transfats (2% of energy), when replaced by MUFA-Ps (Table 1). Additionally, the HRs (95% CIs) were 0.67 (0.61, 0.73; P<0.0001) and 0.78 (0.73, 0.83; P<0.0001), respectively, for replacing 5% of energy in MUFA-As or the sum of SFAs and MUFA-As with MUFA-Ps.Conclusion:In three large prospective cohort studies, higher intakes of MUFA-Ps were associated with a lower risk of T2D, whereas increased intakes of MUFA-As was associated with higher risk. Replacing refined carbohydrates, transfats, and MUFA-As with MUFA-Ps may be beneficial for the prevention of T2D.

Background:Effects of omega-3 fatty acids on the prevention of type 2 diabetes (T2D) are unclear. Relatively few prospective studies have utilized objective omega-3 biomarkers to assess risk.Aims:To assess the prospective relationship between circulating and tissue levels of alpha linoleic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), with respect to risk of T2D.Methods:A global consortium of 20 prospective cohort studies from 14 nations with assessments of ALA, EPA, DPA, or DHA in adults (age > 18 years) were identified through July 2017 and included in this investigation. A pre-specified analytic protocol, including definitions for exposures, covariate list, disease outcome definitions, and subgroup analyses was developed and followed in new participant-level cohort analysis. Associations were pooled using inverse variance-weighted meta-analysis.Results:Among 65,147 participants, 16,693 incident cases of T2D occurred during follow-up (median follow-up in the cohorts ranged from 2.5 to 21.2 years). In pooled multivariate analysis, per interquintile range (difference between the midpoints of the first and fifth quintile for each fatty acid), EPA, DPA, DHA, and their sum (Figure 1) were associated with 8%, 21%, 18%, and 19% lower risk of T2D, respectively (all P<0.001). Higher levels of ALA were not significantly associated with T2D. Associations were consistent across different lipid compartments and pre-specified subgroups, including by age, sex, and geographic region, as well as in several sensitivity analyses.Conclusion:Higher circulating and tissue biomarkers of seafood-derived omega-3 fatty acids, EPA, DPA, and DHA, were associated with lower risk of T2D in a global consortium of prospective studies. Plant-derived ALA was not significantly associated with risk.