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Xylitol showed prothrombotic properties that could elevate consumers’ risk for incident CVD events.

The sugar substitute is commonly used in diabetic confectionaries, gums and toothpaste.

Xylitol, a low-calorie sugar substitute commonly found in gum and toothpaste, demonstrated prothrombotic properties, possibly raising risk for major adverse CV events, researchers reported.

A series of studies, led by Stanley L. Hazen, MD, PhD, chairman for the department of cardiovascular and metabolic sciences in the Lerner Research Institute and co-section head of preventive cardiology at the Cleveland Clinic, demonstrated the potentially adverse CV risks of elevated intake of the artificial sweetener.

“Xylitol is becoming one of the more common ‘carb friendly’ or ‘low calorie’ sugar substitutes, especially for diabetic confectionaries, candies and baking goods. It also is very common in oral care products — it helps prevent dental caries,” Hazen told Healio. “We began our studies looking to identify chemicals in blood that might help us identify new pathways linked to residual CVD risk, the risk that remains once one has treated cholesterol, blood sugar, BP and all of the other risk factors to normal levels, yet still the majority of cardiac events continue to occur, meaning there are additional pathways we have yet to discover that are linked to residual CVD risks. ... Our initial large-scale clinical observation studies identified erythritol, last year, and xylitol, this year.”

Hazen and colleagues’ research involved three separate studies:

verification that higher fasting blood levels of xylitol were associated with increased risk for incident CVD in independent studies with new/non-overlapping patients;

mechanistic studies determining that high levels of xylitol were associated with platelet hyperresponsiveness in patient population studies, and clotting risk in animal models; and

human intervention studies where intake of a typical portion size of xylitol was associated with increased platelet responsiveness in all patients.

“Causal studies show physiological levels of xylitol promote heightened risk for blood clotting, and this is entirely consistent with our large-scale clinical observation studies,” said Hazen, a member of the Healio | Cardiology Today Editorial Board.

Prothrombotic effects of xylitol
In initial untargeted metabolomics studies involving a discovery cohort of 1,157 stable individuals undergoing elective diagnostic cardiac evaluation and a subsequent targeted validation cohort of 2,149 individuals who underwent liquid chromatography-tandem mass spectrometry, the highest tertile of circulating levels of xylitol was associated with 3-year incidence of major adverse CV events (adjusted HR = 1.57; 95% CI, 1.12-2.21; P < .01), after adjustment for traditional CV risk factors and high-sensitivity C-reactive protein, compared with the lowest tertile.

Hazen and colleagues also conducted functional studies to evaluate the effect of xylitol on platelet adhesion to a collagen surface, the initial step in thrombus formation.

Platelet adhesion was observed in human blood under physiological shear flow, and xylitol substantially accelerated the rate of collagen-dependent platelet adhesion, according to the study.

“Our studies show a direct effect of xylitol on the isolated platelets,” Hazen told Healio. “Given that sugar alcohols like xylitol interact with a chemical receptor on the surface of cells — like our tastebuds on our tongues — I speculate there is a receptor on platelets that recognizes sugar alcohols like xylitol and erythritol that lowers the threshold for platelets to respond to agonists, so a submaximal stimulus will trigger a more robust response.”

In a human intervention study, Hazen and colleagues gave 10 healthy volunteers 30 mg xylitol dissolved in water to ingest. Plasma xylitol was measured before and 30 minutes after ingesting the solution.

Xylitol significantly increased postprandial plasma levels by a median of 312 M, and platelet functional analyses showed significant increase in aggregation responses to either adenosine 5-diphosphate or thrombin receptor-activating peptide-6 (P at all doses < .0001).

Moreover, the researchers noted a strong correlation between postprandial xylitol levels and either adenosine 5-diphosphate-induced (Spearman rank correlation, 0.71) or thrombin receptor-activating peptide-6-induced aggregation responses (Spearman rank correlation, 0.74; P for both < .0001).

‘A significant public health concern’
“This represents a significant public health concern. The very same people most likely to be targeted for taking sugar substitutes — those with obesity, diabetes and metabolic syndrome — are the most vulnerable,” Hazen told Healio. “By trying to reach for something healthy, the concern is one is inadvertently adding to cardiac risks.

“I hope this serves as a calling for new regulatory guidelines to improve labeling mandates and remove sugar substitutes like xylitol from “Generally Recognized as Safe” status,” he said.

https://www.healio.com/news/cardiology/20240606/common-sugar-substitute-facilitates-blood-clotting-raising-risk-for-heart-attack-stroke