Ingestion of the Non-Nutritive Sweetener Erythritol, but Not Glucose, Enhances Platelet Reactivity and Thrombosis Potential in Healthy Volunteers-Brief Report

Abstract

Background: Although artificial and non-nutritive sweeteners are widely used and generally recognized as safe by the US and European Union regulatory agencies, there have been no clinical trials to assess either long-term cardiovascular disease risks or short-term cardiovascular disease-relevant phenotypes. Recent studies report that fasting plasma levels of erythritol, a commonly used sweetener, are clinically associated with heightened incident cardiovascular disease risks and enhance thrombosis potential in vitro and in animal models. Effects of dietary erythritol on thrombosis phenotypes in humans have not been examined.

Methods: Using a prospective interventional study design, we tested the impact of erythritol or glucose consumption on multiple indices of stimulus-dependent platelet responsiveness in healthy volunteers (n=10 per group). Erythritol plasma levels were quantified with liquid chromatography tandem mass spectrometry. Platelet function at baseline and following erythritol or glucose ingestion was assessed via both aggregometry and analysis of granule markers released.

Results: Dietary erythritol (30 g), but not glucose (30 g), lead to a >1000-fold increase in erythritol plasma concentration (6480 [5930-7300] versus 3.75 [3.35-3.87] μmol/L; P<0.0001) and exhibited acute enhancement of stimulus-dependent aggregation responses in all subjects, agonists, and doses examined. Erythritol ingestion also enhanced stimulus-dependent release of the platelet dense granule marker serotonin (P<0.0001 for TRAP6 [thrombin activator peptide 6] and P=0.004 for ADP) and the platelet α-granule marker CXCL4 (C-X-C motif ligand-4; P<0.0001 for TRAP6 and P=0.06 for ADP). In contrast, glucose ingestion triggered no significant increases in stimulus-dependent release of either serotonin or CXCL4.

Conclusions: Ingestion of a typical quantity of the non-nutritive sweetener erythritol, but not glucose, enhances platelet reactivity in healthy volunteers, raising concerns that erythritol consumption may enhance thrombosis potential. Combined with recent large-scale clinical observational studies and mechanistic cell-based and animal model studies, the present findings suggest that discussion of whether erythritol should be reevaluated as a food additive with the Generally Recognized as Safe designation is warranted.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04731363.

Keywords: models, animal; non-nutritive sweeteners; platelet aggregation; thrombosis.

Figure 1.. Ingestion of erythritol, but not glucose, enhances platelet responsiveness to multiple agonists in healthy volunteers.

(A, B) Platelet aggregation in response to the indicated concentrations of ADP (top) or TRAP6 (bottom) at baseline (blue) and 30 min post glucose (orange) or erythritol ingestion (red). Multiple replicates of paired samples (connected by lines) from each subject are shown. Boxes represent interquartile range (IQR) with median (thicker line within box). Lower whiskers represent smallest observations (≥25% quantile-1.5×IQR), and upper whiskers represent largest observations (≤75% quantile+1.5×IQR). The total number of paired (baseline/postprandial) replicates from subjects for challenges (glucose or erythritol) are shown. To evaluate difference across groups (erythritol versus glucose, and before versus after consumption), a 2-factor non-parametric p value was calculated using Friedman test. When it was significant, p values for pairwise comparisons were performed with Wilcoxon signed rank test.

Figure 2.. Ingestion of erythritol, but not glucose, increases agonist-induced platelet alpha and dense granule release.

(A, B) Erythritol ingestion enhances platelet stimulus-dependent release of both alpha granule (CXCL4) and dense granule (serotonin) products in response to sub-maximal levels of agonists (ADP(2 μM), panel A; and TRAP6 (7.5 μM), panel B) in healthy volunteers. Platelet release of CXCL4 (ELISA) and serotonin (LC-MS/MS) in response to the indicated concentration of ADP or TRAP6 at baseline (blue) and 30 min post ingestion of 30 g of either erythritol (red) or glucose (orange). The total number of paired (baseline/postprandial) replicates from the indicated number of subjects for both challenges are shown. Bars represent median levels in each group. To evaluate difference across groups (erythritol versus glucose, and before versus after consumption), a 2-factor non-parametric p value was calculated using Friedman test. When it was significant, p values for pairwise comparisons were performed with Wilcoxon signed rank test.