Sugar substitutes linked to heart and blood clot risks

A series of studies have found that the popular low-calorie sweetener xylitol is associated with an increased risk of cardiovascular disease and thrombosis.

A metabolomic study found that xylitol intake was associated with an increased risk of major adverse cardiovascular events (MACE), with a 57-80% higher relative risk in the top and bottom tertiles of blood concentration, even after adjusting for other factors (P≤0.03), said Stanley L. Hazen, MD, of the Lerner Research Institute at the Cleveland Clinic. European Heart Journal.

Mechanistic studies in animal models have shown that xylitol increases platelet reactivity and in vivo clot formation.

And an intervention study of 10 healthy subjects confirmed that this happens in humans: Ingestion of a standard amount of a xylitol-sweetened beverage had a rapid and significant effect on all measures of platelet activation in all subjects compared with drinking a sugar-sweetened beverage.

“This study reinforces the urgent need to investigate sugar alcohols and artificial sweeteners, especially as they continue to be promoted to combat conditions such as obesity and diabetes,” Hazen said. In a press release“There is no need to throw away your toothpaste just because it contains xylitol, but people should be aware that consuming products high in xylitol may increase the risk of blood clot-related events.”

Xylitol is a sugar alcohol found naturally in foods such as strawberries, spinach, and cauliflower, but is usually made commercially from corn cobs, birch, or genetically modified bacteria. It is commonly used in sugarless gum, breath mints, and toothpaste, and is also added to processed foods. The FDA classifies xylitol as “Generally recognized as safe“Therefore, there is no need to list the amount added on food labels.”

“For many years, both the scientific community and the general public have been convinced that artificial sweeteners are beneficial because they reduce excess sugar intake, reduce calorie intake, especially from soft drinks, reduce weight gain and, as the implicit claim goes, reduce the risk of cardiovascular disease,” Jürg Bier, MD, PhD, and Meret Allemann, MSc, of the Platelet Institute at the University of Zurich, wrote in an accompanying paper. editorial.

The study raises “an important, timely and serious warning signal,” the researchers wrote, “and unfortunately, these sugars are frequently used in real life among patient groups at risk for obesity and diabetes.”

And the concerns appear to extend to other sugar alcohols used as sweeteners, such as erythritol.

Hazen's group previously A similar analysis of erythritol They also showed a 1.8- to 2.2-fold relative increased risk of MACE in those in the top quartile compared with those in the bottom quartile.They also found that after healthy volunteers consumed normal amounts of erythritol-sweetened beverages, plasma erythritol concentrations rose significantly above thresholds associated with increased platelet reactivity and thrombus potential and remained so for several days.

Other studies have shown that consumption of artificially sweetened beverages Onset of atrial fibrillation (10-year adjusted HR for those consuming approximately 8.5 cups of coffee per week was 1.20, 95% CI 1.10-1.31) compared with non-consumers.

Hazen and colleagues' xylitol study began with untargeted metabolomic analysis performed on overnight fasting plasma samples in a discovery cohort of 1,157 consecutive stable patients undergoing elective diagnostic cardiac evaluation. The association between xylitol and MACE was subsequently confirmed in an independent, non-overlapping validation cohort of 2,149 individuals by xylitol-specific stable isotope dilution liquid chromatography–tandem mass spectrometry analysis.

In experiments with isolated human platelets, platelet-rich plasma, whole blood, and animal models, increased platelet adhesion under flow, enhanced activation of glycoprotein IIb/IIIa, and p-selectin expression by flow cytometry were observed after the addition of xylitol. In a mouse carotid artery thrombosis model, exposure to xylitol increased calcium mobilization and platelet-leukocyte aggregation and reduced occlusion times.

A subsequent challenge study in 10 healthy volunteers showed that a soft drink containing 30 grams of xylitol increased platelet reactivity within 30 minutes of ingestion compared with a sugar-sweetened drink, “strongly suggesting a causal relationship,” the editorialists noted.

“The data and myriad questions call for both regulators and researchers to further explore whether sugar alcohol sweeteners are harmful to cardiovascular health,” Beer and Aleman concluded. “Confirmatory studies, longer exposure analyses, and mechanistic elucidation will be needed to support these less clear-cut perspectives regarding the widespread use of sugar alcohols.”

Hazen's group cautioned that the findings from the observational cohort study could not establish causation of the MACE events, there were no dietary data, and the mechanistic studies, while claiming direct effects, focused on relatively short-term exposure to xylitol and could not comment on the effects of chronic exposure.