Sugar Alcohol Xylitol Associated with Increased Risk of MACE: Cleveland Clinic Research

Higher amounts of the sugar alcohol xylitol were associated with increased risk of major adverse cardiovascular events (MACE), such as heart attack and stroke, a recent study found.

The study, from investigators at the Cleveland Clinic, was published in the European Heart Journal.¹

“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,” study author Stanley Hazen, MD, PhD, chair of cardiovascular and metabolic sciences at Cleveland Clinic’s Lerner Research Institute and co–section head of preventive cardiology in the Heart, Vascular & Thoracic Institute, said in a press release.² “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 substitute commonly used in sugar-free candy, gums, baked goods, and oral products like toothpaste. The use of sugar substitutes has increased significantly in processed foods as these products have been promoted as healthier alternatives to sugar.

Hazen and colleagues, however, published research last year identifying a link between erythritol and cardiovascular risk in a study last year. They aimed in the current study to evaluate the potential link between xylitol and residual cardiovascular disease risks.¹

The researchers performed 3 distinct clinical studies with nonoverlapping human participants (n = 1157) and a validation cohort (n = 2149). Blood samples from healthy volunteers were collected for platelet-related studies, including aggregometry studies in platelet-rich plasma, intracellular calcium measurements, platelet flow cytometry assay, imaging flow cytometry in whole blood, whole-blood in vitro thrombosis assay, carotid artery FeCI3 injury model, and untargeted and targeted mass spectrometry analysis of human plasma.

At baseline, participants in the discovery cohort had a median (IQR) age of 65 (56-72) years, 64% were male, and median (IQR) body mass index was 28.4 (25.4-32.1) kg/m2. Additionally, 22% of participants in this cohort had diabetes, 72% had hypertension, and 14% were current smokers.

In the discovery cohort, circulating levels of a polyol tentatively assigned as xylitol were associated with incident (3-year) MACE risk. In the validation cohort, subsequent mass spectrometry analysis specific for xylitol confirmed the association of incident MACE risk, finding that a third of participants with the highest amount of xylitol in their plasma were more likely to experience a cardiovascular event (third vs first tertile adjusted HR, 1.57; 95% CI, 1.12-2.21; P <.01).

Furthermore, the researchers conducted preclinical testing to confirm these findings. Complementary mechanistic studies showed xylitol enhanced multiple indices of platelet reactivity and in vivo thrombosis formation at levels observed in fasting plasma. Moreover, when tracking platelet activity after consumption of a xylitol-based sweetened drink, the researchers identified raised plasma levels and enhanced measures of platelet responsiveness in all subjects.

Investigators did acknowledge some limitations to the studies. First, there was no information on xylitol dietary exposure in the clinical observational cohorts. Second, the participants enrolled in the validation cohort largely predate the more recent increases in dietary exposure to xylitol in processed foods. And, the researchers only measured baseline fasting levels of xylitol in the clinical cohort studies, with participants having a higher burden of cardiovascular risk factors compared with the general population.

Despite these limitations, the researchers believe the study suggests that xylitol is linked to increased MACE risk, and that further studies are needed to assess the long-term safety of xylitol.

“Our studies suggest that xylitol will likely confer heightened thrombosis potential in the same vulnerable participants that it is marketed towards and intended to protect,” wrote the researchers.

References
1. Witkowski M, Nemet I, Li X, et al. Xylitol is prothrombotic and associated with cardiovascular risk. Eur Heart J. Published online June 6, 2024. doi.org/10.1093/eurheartj/ehae244
2. Cleveland Clinic-led study links sugar substitute to increased risk of heart attack and stroke. News release. June 6, 2024. Accessed June 11, 2024. https://newsroom.clevelandclinic.org/2024/06/06/cleveland-clinic-led-study-links-sugar-substitute-to-increased-risk-of-heart-attack-and-stroke