Background Circulating branched-chain amino acids (BCAAs; isoleucine, leucine, valine) are strong predictors of type 2 diabetes (T2D), but their association with cardiovascular disease (CVD) is uncertain. We hypothesized that plasma BCAAs are positively associated with CVD risk, and evaluated whether this was dependent on an intermediate diagnosis of T2D. Methods Participants enrolled in the Women’s Health Study prospective cohort were eligible if free of CVD at baseline blood collection (N=27,041, mean baseline age=54.7 years). Plasma BCAA metabolites were measured via NMR spectroscopy, ln-transformed, and standardized for analysis. Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs for total and individual BCAAs with incident CVD (myocardial infarction [MI], stroke, coronary revascularization). Results We confirmed 2,207 CVD events over a mean 18.6 years of follow-up. Adjusting for age, BMI, smoking, diet, physical activity, and other established CVD risk factors, total BCAAs were positively associated with CVD (per SD HR=1.13, CI=1.08 to 1.18), comparable in magnitude to modeling the association of LDL cholesterol with CVD (per SD HR=1.12, CI=1.07 to 1.17). In particular, BCAAs were associated with coronary events (MI: per SD HR=1.16, CI=1.06 to 1.26; revascularization: per SD HR=1.17, CI=1.11 to 1.25), but not with stroke (per SD HR=1.07, CI=0.99 to 1.15). Isoleucine, leucine, and valine were each separately associated with CVD (p<0.05). The BCAA-CVD association was greater (p-interaction=0.036) among women who developed T2D prior to CVD (HR=1.20, CI=1.08 to 1.32), vs. women without T2D (HR=1.08, CI=1.03 to 1.14). Adjusting for LDL-C, an established CVD risk factor, did not attenuate these findings; however, adjusting for HbA1c and insulin resistance, cardiometabolic biomarkers that may be downstream mediators of risk, eliminated the associations of BCAAs with CVD. Conclusions Circulating plasma BCAAs were positively associated with incident CVD in a prospective cohort of US women. Impaired BCAA metabolism may represent a shared pathway of metabolic dysfunction that links T2D and CVD, and plasma BCAAs may capture the long-term cardiometabolic risks of this common etiology, in particular among women who develop T2D prior to a CVD event.

BackgroundIt is uncertain whether pharmacological reductions in very‐low‐density lipoproteins (VLDLs), and their component triglyceride and cholesterol could reduce residual risk of atherosclerotic cardiovascular disease (ASCVD) events among individuals in whom low‐density lipoprotein cholesterol (LDL‐C) has been adequately lowered. We examined whether individuals with greater on‐statin reductions in VLDL‐related measures—beyond reductions in LDL‐C—were at further reduced risk of ASCVD.Methods and ResultsIn 9423 participants in the JUPITER (Justification for the Use of Statins in Prevention) trial (NCT00239681), at baseline and on statin we measured standard lipids, 400‐MHz proton nuclear magnetic resonance spectroscopy‐measured VLDL particle subclasses (small, medium, and large VLDL lipoprotein particle concentration), and total VLDL cholesterol mass. Compared with individuals allocated to placebo, we examined risk of incident ASCVD (N=211) among statin‐allocated participants who achieved minimal (

Background Type 2 diabetes (T2D) is preceded by prolonged insulin resistance and relative insulin deficiency incompletely captured by glucose metabolism parameters, HDL-c and triglycerides. Objective Whether lipoprotein insulin resistance score (LPIR), a metabolomic marker, is associated with incident diabetes and improve risk reclassification over traditional markers on extended follow up. Methods Among 25,925 non-diabetic women aged 45 years or older, LPIR was measured by nuclear magnetic resonance spectroscopy as a weighted score of VLDL, LDL and HDL particle sizes, and their subsets concentrations. We run adjusted cox regression models for LPIR with incident T2D (20.4 years median follow-up). Results Adjusting for demographics, body mass index (BMI), life style factors, blood pressure and T2D family history, the LPIR hazard ratio for T2D (HR per SD, 95% confidence interval [CI]) was 1.95 (1.85, 2.06). Further adjusting for HbA1c, C-reactive protein, triglycerides, HDL and LDL cholesterol, LPIR HR was attenuated to 1.41 (1.31, 1.53) and had the strongest association with T2D after HbA1C in mutually adjusted models. The association persisted even in those with optimal clinical profiles, adjusted HR per SD 1.91 (1.17, 3.13). In participants deemed at intermediate T2D risk by the Framingham Offspring T2D score, LPIR led to a net reclassification of 0.145 (0.117, 0.175). Conclusion In middle aged or older healthy women followed prospectively over 20 years, LPIR was robustly associated with incident T2D, including among those with an optimal clinical metabolic profile. LPIR improved T2D risk classification and may guide early and targeted prevention strategies.