Artificial sweeteners are widely used sugar substitutes, but little is known about their long-term effects on cardiometabolic disease risks. Here we examined the commonly used sugar substitute erythritol and atherothrombotic disease risk. In initial untargeted metabolomics studies in patients undergoing cardiac risk assessment (n = 1,157; discovery cohort, NCT00590200 ), circulating levels of multiple polyol sweeteners, especially erythritol, were associated with incident (3 year) risk for major adverse cardiovascular events (MACE; includes death or nonfatal myocardial infarction or stroke). Subsequent targeted metabolomics analyses in independent US (n = 2,149, NCT00590200 ) and European (n = 833, DRKS00020915 ) validation cohorts of stable patients undergoing elective cardiac evaluation confirmed this association (fourth versus first quartile adjusted hazard ratio (95% confidence interval), 1.80 (1.18-2.77) and 2.21 (1.20-4.07), respectively). At physiological levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo. Finally, in a prospective pilot intervention study ( NCT04731363 ), erythritol ingestion in healthy volunteers (n = 8) induced marked and sustained (>2 d) increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies. Our findings reveal that erythritol is both associated with incident MACE risk and fosters enhanced thrombosis. Studies assessing the long-term safety of erythritol are warranted.

Berlin Institute of Health Berlin Germany

Berlin Institute of Health Center for Regenerative Therapies Berlin Germany

Department of Cardiology Angiology and Intensive Care German Heart Center of Charité Campus Benjamin Franklin Berlin Germany

Department of Cardiovascular and Metabolic Sciences Lerner Research Institute Cleveland Clinic Cleveland OH USA

Department of Clinical Laboratory Sciences College of Applied Medical Sciences King Saud bin Abdulaziz University for Health Sciences Riyadh Saudi Arabia

Department of Endocrinology and Metabolism Charité Universitätsmedizin Berlin Berlin Germany

Department of Mathematics and Statistics Cleveland State University Cleveland OH USA

Friede Springer Cardiovascular Prevention Center at Charité Berlin Germany

German Center for Cardiovascular Research Partner Site Berlin Berlin Germany

Heart Vascular and Thoracic Institute Cleveland Clinic Cleveland OH USA

Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

West Coast Metabolomics Center University of California Davis CA USA

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Nat Rev Cardiol. 2023 May;20(5):283. doi: 10.1038/s41569-023-00855-5. PubMed

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Clin Chem. 2023 Oct 3;69(10):1098-1100. doi: 10.1093/clinchem/hvad069. PubMed

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