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The artificial sweetener erythritol and cardiovascular event risk

Nature Medicine volume 29, pages 710–718 (2023)Cite this article

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Abstract

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.

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Fig. 1: Kaplan–Meier estimates and forest plots indicating the risks of MACE, according to erythritol quartile level.
Fig. 2: Long-term risk of MACE among patient subgroups.
Fig. 3: Erythritol enhances platelet responsiveness.
Fig. 4: Erythritol enhances in vivo thrombosis formation.
Fig. 5: Effects of an erythritol challenge on mean plasma levels.

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Data availability

There are restrictions to the availability of some of the clinical data generated in the present study (Figs. 1 and 2), because we do not have permission in our informed consent from research subjects to share data outside our institution without their authorization. Where permissible, the datasets generated and/or analyzed during the present studies are available from the corresponding author Stanley L. Hazen (hazens@ccf.org) on request. An answer can be expected within 14 d.

Code availability

Custom R codes used in this manuscript are available at ‘https://doi.org/10.5281/zenodo.6780497’. The BinBase database is accessible using the following link ‘https://bitbucket.org/fiehnlab/binbase/src/master/?’.

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Acknowledgements

This work is supported by grants from the NIH and Office of Dietary Supplements P01 HL147823, R01 HL103866 (S.L.H.), the Leducq Foundation 17CVD01 (S.L.H. and U.L.) and the Deutsche Forschungsgemeinschaft WI 5229/1-1 (M.W.). A.H. is a participant in the BIH-Charité Advanced Clinician Scientist Program funded by the Charité—Universitätsmedizin Berlin and the Berlin Institute of Health. The LipidCardio Study was partially funded by the Sanofi-Aventis Deutschland GmbH (I.D. and U.L.). P.P.S. was supported in part by an AHA postdoctoral grant 20POST35210937. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank G. Deshpande (Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic) for technical support during whole blood in vitro thrombosis studies. We also thank M. Ferrell for assistance in data analysis and T. Weeks (both at the Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic) for editing the manuscript.

Author information

Author notes

  1. Hassan Alamri

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

  2. Tomas Cajka

    Present address: Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic

  3. These authors contributed equally: Marco Witkowski, Ina Nemet.

Authors and Affiliations

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

    Marco Witkowski, Ina Nemet, Hassan Alamri, Jennifer Wilcox, Nilaksh Gupta, Nisreen Nimer, Xinmin S. Li, Yuping Wu, Prasenjit Prasad Saha, W. H. Wilson Tang & Stanley L. Hazen

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

    Arash Haghikia & Ulf Landmesser

  3. German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany

    Arash Haghikia & Ulf Landmesser

  4. Berlin Institute of Health (BIH), Berlin, Germany

    Arash Haghikia & Ulf Landmesser

  5. Friede Springer Cardiovascular Prevention Center at Charité, Berlin, Germany

    Arash Haghikia & Ulf Landmesser

  6. Department of Mathematics and Statistics, Cleveland State University, Cleveland, OH, USA

    Yuping Wu

  7. Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Ilja Demuth, Maximilian König & Elisabeth Steinhagen-Thiessen

  8. Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany

    Ilja Demuth

  9. West Coast Metabolomics Center, University of California, Davis, CA, USA

    Tomas Cajka & Oliver Fiehn

  10. Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA

    W. H. Wilson Tang & Stanley L. Hazen

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Contributions

M.W. participated in the design of all in vitro and in vivo studies, performed experiments and statistical analysis and drafted the manuscript. M.W. and I.N. wrote the manuscript with input from all authors. I.N. and H.A. developed and performed the mass spectrometry analysis in human and mouse samples. N.N. helped with mass spectrometry analysis. J.W. and M.W. coordinated the Cosette study. N.G. performed whole blood in vitro thrombosis assays. P.P.S. helped with calcium studies. T.C. and O.F. performed untargeted metabolic analysis. Y.W. and X.S.L. analyzed data. A.H., I.D., M.K., E.S.-T. and U.L. contributed clinical study samples and assisted with data analysis from the European validation cohort. W.H.W.T. coordinated the Cosette study and provided critical scientific input and discussions. S.L.H. conceived, designed and supervised all experiments and participated in the drafting and editing of the article. All authors contributed to the critical review of the manuscript.

Corresponding author

Correspondence to Stanley L. Hazen.

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Competing interests

Hazen reports being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics, being a paid consultant formerly for Procter and Gamble and currently with Zehna Therapeutics. He also reports having received research funds from Procter and Gamble, Zehna Therapeutics and Roche Diagnostics, and being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, a wholly owned subsidiary of Quest Diagnostics, Procter and Gamble and Zehna therapeutics. Tang reports being a consultant for Sequana Medical A.G., Owkin Inc., Relypsa Inc. and PreCardiac Inc., having received an honorarium from Springer Nature for authorship/editorship and American Board of Internal Medicine for exam writing committee participation—all unrelated to the subject and contents of this paper. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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Extended data

Extended Data Fig. 1 Polyol metabolites and major adverse cardiovascular events (MACE) in untargeted metabolomics analyses of the discovery cohort.

Shown are boxplots with relative levels for the indicated polyol (defined as compounds with two or more hydroxyl groups) area in both patients with (red) and without (blue) incident (3 yr) MACE ranked by Mann Whitney P values. Compound relative areas are shown as log of fold change (no MACE vs. MACE) to facilitate comparison. Boxes represent interquartile ranges (IQR) with the notch indicating the median. Lower whiskers represent smallest observation (≥25% quantile -1.5×IQR) and upper whiskers largest observation (≤75% quantile +1.5×IQR). Two-sided P values were calculated by Mann–Whitney U-test. N for no MACE = 1041, n for MACE = 116. False discovery rate corrected two-sided P values (Benjamini-Hochberg method) are indicated as follows: ****P<0.0001, ***P < 0.001, **P < 0.01, *P < 0.05.

Extended Data Fig. 2 Chromatographic separation of erythritol from its structural isomer threitol.

After exhaustive acetylation with acetic acid anhydride, the polyols erythritol and its structural isomer, threitol, were baseline resolved by the HPLC method developed. Shown are the chromatograms generated by multiple reaction monitoring transitions (MRM) for the derivatized plasma analytes (m/z 308; [M+NH4]+) and synthetic isotopically labeled erythritol internal standard (D6-Erythritol; m/z 314; [M+NH4]+). With the column matrix and mobile phase /gradient employed, coupled with the characteristic parent [M+NH4+] —> daughter ion transition used (for both erythritol and threitol), baseline chromatographic resolution of the two structural isomers was achieved.

Extended Data Fig. 3 Plasma levels of erythritol are elevated in patients with major adverse cardiovascular events (MACE) and coronary artery disease (CAD) in both US and European validation cohorts.

Erythritol levels in patients stratified by presence of (3 year) MACE or CAD. Data are shown as log of plasma Erythritol. Plotted are individual values as dots. Boxes represent interquartile ranges (IQR) with the notch indicating the median. Lower whiskers represent smallest observation (≥25% quantile - 1.5×IQR) and upper whiskers largest observation (≤75% quantile + 1.5×IQR). Two-sided P values were calculated by Mann–Whitney U-test. Numbers of subjects within each group are indicated.

Extended Data Fig. 4 Erythritol increases platelet aggregation responses to submaximal concentrations of agonists.

ADP-stimulated and Thrombin receptor-activating peptide(TRAP)6-stimulated platelet aggregometry responses of human platelet-rich plasma with fixed concentration of erythritol (45 or 90 μM, red) versus normal saline (vehicle, blue). Data in bar graphs are represented as means (±s.d.), and two-sided P values were calculated by Mann Whitney Test (bar graphs) and by 2-way analysis of variance (overall P value is shown for erythritol effect) with Sidák’s post hoc test. Sidák’s adjusted P values for Erythritol 45 μM vs. vehicle: for ADP 2 μM P = 0.01, ADP 3 μM P = 0.005, for erythritol 90 μM vs. vehicle: TRAP6 5 μM: P = 0.0002. Numbers of independent biological replicates (n) are indicated. *P < 0.05, ** P < 0.01, ***P < 0.001.

Extended Data Fig. 5 Impact of glucose on platelet aggregation.

ADP-stimulated (left panel) and Thrombin receptor-activating peptide (TRAP) 6-stimulated (right panel) platelet aggregometry responses in human platelet-rich plasma incubated with glucose (270 μM, green) versus vehicle (saline, blue). Data in bar graphs are represented as means (±s.d.). Two-sided P values were calculated using Mann–Whitney U-test. Numbers of independent biological replicates (n) are indicated.

Extended Data Fig. 6 Impact of 1,5-Anhydroglucitol (AHG) on platelet aggregation and calcium release.

Panel A ADP-stimulated and Thrombin receptor-activating peptide (TRAP)6-stimulated platelet aggregometry responses in human platelet-rich plasma incubated with 1,5-AHG (green) versus vehicle (saline, blue). Two-sided P values were calculated by Mann Whitney Test. For ADP and TRAP6 stimulated platelet-rich plasma n = 7. Panel B shows thrombin-induced (0.02 U ml−1) changes in intracellular calcium concentration in Fura 2-filled washed human platelets incubated with 1,5-AHG (green) or vehicle (saline, blue). Data represent mean (±s.d.). Two-sided P values were calculated by Wilcoxon matched-pairs signed rank test. Numbers of independent biological replicates (n) are indicated.

Extended Data Fig. 7 Impact of 1,5-Anhydroglucitol (AHG) and glucose on platelet activation.

ADP-induced changes in GP IIb/IIIa (PAC-1 antibody staining) and P-selectin surface expression in washed human platelets pre-incubated with vehicle (saline, blue) or the indicated concentrations of either 1,5-AHG (green, panel A) or glucose (green, panel B). Bars represent means (±s.d.), Two-sided P values were calculated by Kruskal–Wallis test with Dunn’s post hoc test for multiple-group comparisons. Numbers of independent biological replicates (n) are indicated.

Extended Data Fig. 8 Impact of erythritol at different physiological concentrations on platelet aggregation responses.

Human platelet-rich plasma was incubated with erythritol (red) at low levels observed in fasting patients (18 μM) and higher concentrations observed after erythritol ingestions (6 mM) versus vehicle (saline, blue). Shown are thrombin receptor-activating peptide(TRAP)6-stimulated (panel A) and ADP-stimulated (panel B) platelet aggregometry responses. Data in bar graphs are represented as means (±s.d.). Two-sided P values were calculated by Mann Whitney Test. Numbers of independent biological replicates (n) are indicated.

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Witkowski, M., Nemet, I., Alamri, H. et al. The artificial sweetener erythritol and cardiovascular event risk. Nat Med 29, 710–718 (2023). https://doi.org/10.1038/s41591-023-02223-9

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