Plasma metabolomic profiles associated with cardiovascular disease in type 2 diabetes from the Trans-Omics for Precision Medicine (TOPMed) program

Authors: ZHANG, YIXIN - Boston University School Of Public Health; NGUYEN, NGOC - University Of Texas Health Science Center; HANSON, PAUL - Massachusetts General Hospital; SEVILLA-GONZALEZ, MAGDALENA - Massachusetts General Hospital; HAESSLER, JEFFREY - Fred Hutchinson Cancer Research Center; SARNOWSKI, CHLOE - University Of Texas Health Science Center; YAO, JIE - Harbor-Ucla Medical Center; YU, BING - University Of Texas Health Science Center; JAMSHIDI, AFSHIN - McGill University - Canada; BOERWINKLE, ERIC - University Of Texas Health Science Center; BROWN, MICHAEL - University Of Texas Health Science Center; CHEN, ZSU - Beth Israel Deaconess Medical Center; CHEN, YII - Harbor-Ucla Medical Center; CLISH, CLARY - Broad Institute Of Mit/harvard; DICORPO, DANIEL - Boston University School Of Public Health; DURDA, PETER - University Of Vermont; GERTSZEN, ROBERT - Broad Institute Of Mit/harvard; GOODARZI, MARK - Cedars-Sinai Medical Center; GUO, XIUQING - Harbor-Ucla Medical Center; HEARD-COSTA, NANCY - Framingham Heart Study; JOHNSON, W - University Of Washington; KOOPERBERG, CHARLES - Fred Hutchinson Cancer Research Center; PANKOW, JAMES - University Of Minnesota; POST, WENDY - Johns Hopkins University; REINER, ALEXANDER - University Of Washington; RICH, STEPHEN - University Of Virginia School Of Medicine; ROTTER, JEROME - Harbor-Ucla Medical Center; DE VRIES, PAUL - University Of Texas Health Science Center; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); TAYLOR, KENT - Harbor-Ucla Medical Center; MANNING, ALISA - Massachusetts General Hospital; DUPUIS, JOSEE - Boston University School Of Public Health; MEIGS, JAMES - Broad Institute Of Mit/harvard; LIU, CHING - Boston University School Of Public Health

Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/13/2026
Publication Date: 4/26/2026
Citation: Zhang, Y., Nguyen, N.Q., Hanson, P.A., Sevilla-Gonzalez, M., Haessler, J., Sarnowski, C., Yao, J., Yu, B., Jamshidi, A., Boerwinkle, E., Brown, M.R., Chen, Z.Z., Chen, Y.D., Clish, C., DiCorpo, D., Durda, P., Gertszen, R., Goodarzi, M.O., Guo, X., Heard-Costa, N.L., Johnson, W.C., Kooperberg, C., Pankow, J.S., Post, W.S., Reiner, A.P., Rich, S.S., Rotter, J.I., de Vries, P.S., Wood, A.C., Taylor, K.D., Manning, A.K., Dupuis, J., Meigs, J.B., Liu, C.T. 2026. Plasma metabolomic profiles associated with cardiovascular disease in type 2 diabetes from the Trans-Omics for Precision Medicine (TOPMed) program. Atherosclerosis. 417. Article 120758. https://doi.org/10.1016/j.atherosclerosis.2026.120758.
DOI: https://doi.org/10.1016/j.atherosclerosis.2026.120758

Interpretive Summary: People with type 2 diabetes are much more likely to develop cardiovascular disease, but the biological reasons for this increased risk are not fully understood. This study examined whether small molecules in the blood, called metabolites, can help explain why some people with diabetes develop heart disease while others do not. In the largest analysis of its kind to date, using data from several large US studies, eight key metabolites linked to cardiovascular disease, including markers related to inflammation, oxidative stress, and lipid metabolism were identified in people with type 2 diabetes. These metabolites were also connected to conditions like obesity and kidney disease, suggesting shared biological pathways that contribute to disease risk. Overall, the findings help clarify how metabolic changes in diabetes may lead to heart disease and highlight potential biomarkers for identifying high-risk individuals. This work is relevant for clinicians, researchers, and policymakers because it supports the development of more precise tools for predicting and preventing cardiovascular complications in people with diabetes.

Technical Abstract: People with Type 2 diabetes (T2D) are twice as likely to develop cardiovascular disease (CVD), though not all excess risk has been fully elucidated. Plasma metabolomics profiles shared between these conditions may uncover molecular mechanisms linking T2D to CVD. We conducted a cross-sectional case-control analysis, comparing T2D individuals who had prevalent CVD to those without CVD at the time of metabolite measurement. Using untargeted liquid chromatography-mass spectrometry (LC-MS), we collected 522 metabolite abundances measured in 1374 participants with T2D (224 CVD cases) from the Trans-Omics for Precision Medicine (TOPMed) program. We used a mixed effects linear model to assess the association of CVD events with each metabolite abundance, adjusting for key covariates. Metabolites meeting a suggestive significance threshold were examined using metabolite set enrichment analysis and evaluated for replication in an independent cohort Atherosclerosis Risk in Communities (ARIC) (n = 1891; 214 CVD cases). We performed meta-analysis to combine both the discovery and replication associations, and assessed overall significance using an experiment-wide Bonferroni-corrected threshold. Metabolites meeting a suggestive threshold were enriched in metabolite sets linked to obesity and kidney disease. Meta-analysis identified eight metabolites reaching experiment-wide significance, confirming previously established associations of asymmetric dimethylarginine, phosphatidylcholines, and gluconic acid, while additionally identifying specific phosphatidylethanolamine species, N-acetyl-L-methionine, and allantoin associated with prevalent CVD among individuals with T2D. Our results established and replicated metabolite associations with prevalent CVD in people with T2D. These metabolites may help characterize metabolic alterations underlying cardiovascular complications that arise in T2D.