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The popular low-calorie sweetener xylitol was linked to increased cardiovascular and thrombotic risk, a series of experiments showed.

Metabolomic studies linked xylitol intake to higher risk for major adverse cardiovascular events (MACE), with a relative 57-80% higher risk for the top versus bottom blood-level tertiles after adjustment for other factors (P≤0.03), Stanley L. Hazen, MD, PhD, of the Lerner Research Institute at the Cleveland Clinic, reported in the .

Mechanistic animal model studies showed that xylitol raised platelet reactivity and in vivo thrombosis formation.

And an intervention study in 10 healthy individuals affirmed the same thing happens in humans. Consuming a typical dose of xylitol-sweetened drink rapidly and significantly impacted every measure of platelet activation in every volunteer compared with drinking a sugar-sweetened beverage.

"This study again shows the immediate need for investigating sugar alcohols and artificial sweeteners, especially as they continue to be recommended in combatting conditions like obesity or diabetes," Hazen said . "It does not mean throw out your toothpaste if it has xylitol in it, but we should be aware that consumption of a product containing high levels could increase the risk of blood clot related events."

Xylitol is a sugar alcohol found naturally in strawberries, spinach, cauliflower, and other foods but is typically made commercially from corncobs, birch trees, or genetically engineered bacteria. It's often used in sugarless gum, breath mints, toothpaste, and added to processed foods. The FDA classifies xylitol as "" and thus doesn't require food labels to disclose how much has been added.

"For many years the scientific community and the general population alike were convinced that artificial sweeteners were beneficial because they reduce excessive sugar intake, and hence reduce ingested calories, particularly from soft drinks, thus reducing weight gain and -- as implicitly argued -- cardiovascular risk," wrote Juerg Beer, MD, and Meret Allemann, MSc, both of the University of Zurich Laboratory for Platelet Research, in an accompanying .

The study sends "an important, timely, and serious warning signal," they noted. "Unfortunately, these sugars are indeed frequently used in the patient group at risk with obesity and diabetes."

And the concern appears to extend to other sugar alcohols used as sweeteners, such as erythritol.

Hazen's group previously conducted a similar series of analyses for erythritol and showed a relative 1.8- to 2.2-fold increase in MACE risk among people in the top versus bottom quartile. They also found plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential that persisted for days after challenging healthy volunteers with a typical dose of an erythritol-sweetened drink.

Other studies have linked artificially sweetened beverage intake to a modestly elevated risk of incident atrial fibrillation (adjusted HR 1.20 over 10 years for consumption of about 8.5 cups per week, 95% CI 1.10-1.31) compared with nonconsumers.

Hazen and colleagues' xylitol research started with analysis of untargeted metabolomics performed on overnight fasting plasma samples in a discovery cohort of 1,157 of sequential stable patients undergoing elective diagnostic cardiac evaluations. Subsequent stable-isotope-dilution liquid chromatography with tandem mass spectrometry analyses specific for xylitol confirmed its association with MACE in an independent, non-overlapping validation cohort of 2,149 individuals.

Experiments with isolated human platelet, platelet-rich plasma, whole blood, and animal models showed increased platelet adhesion under flow, augmented activation of glycoprotein IIb/IIIa, and expression of p-selectin was observed using flow cytometry after addition of xylitol. In a mouse carotid thrombosis model, xylitol exposure increased calcium mobilization and platelet-leukocyte aggregates and shortened occlusion times.

Then a challenge study in 10 healthy human volunteers showed that a soft drink with 30 g of xylitol increased platelet reactivity as early as 30 minutes after ingestion compared with a sugar-sweetened drink, "strongly suggesting causality," the editorialists noted.

"The data and a myriad of questions collectively call for a closer look by the authorities and researchers alike at sugar alcohol sweeteners as a cardiovascular hazard," Beer and Allemann concluded. "Confirmatory studies, longer exposure analyses, and elucidations of mechanisms will have to confirm these not-so-clear skies for the widespread use of sugar alcohols."

Hazen's group cautioned that their observational cohort findings couldn't establish causality in MACE events, nor did they have dietary data. And the mechanistic studies, while arguing for a direct effect, focused on a relatively brief exposure of xylitol without being able to comment on the impact of chronic exposures.

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