Almost a year after my colleague, Dr. Dinerstein, pointed out flaws in a study that observed increased blood clots after ingesting erythritol, we now face a new study from the same group, focusing on xylitol, another sugar alcohol. According to the experiment's results, xylitol promotes blood clot formation and is associated with cardiovascular complications
Market research estimates that the xylitol market reached a value of $701.5 million in 2022 and is projected to grow, indicating substantial interest in the ingredient. Evidence of xylitol harm could significantly influence how the public and companies approach this sweetener. Instead of initiating a reasoned debate as to the reliability of the data, traditional news portals exploited this supposed harmful outcome by publishing articles with sensationalist titles, spreading misinformation, and creating thousands of anxious, concerned consumers.
Based on my reading of the research, these findings are significant and raise hypotheses, but they should be taken with a grain of salt.
After All, what is xylitol:
Xylitol is a sugar alcohol with a low caloric value glycemic index. It is widely used by the food industry as an additive to improve the flavor, texture, and shelf life of sweets, chocolates, and chewing gums, among others. In the pharmaceutical industry, it is used to manufacture toothpaste due to its anti-cariogenic effect, protective action against tooth decay, and the production of cough syrups.
Because it has a sweetening power similar to sugar and does not leave an aftertaste, xylitol has gained popularity among people seeking alternatives to sugar. Furthermore, due to its low glycemic index, the ability to avoid causing abrupt spikes in blood glucose levels, it can be recommended for people with diabetes.
Although most of its production worldwide is achieved through chemical processing, xylitol is “natural,” found in
- Fruits, such as strawberries and bananas
- Vegetables, such as carrots and onions
- And, critically, in analyzing this study, inside our bodies. A healthy individual with a normal metabolism can produce 5 to 15 grams of xylitol daily.
Xylitol is classified as a GRAS (Generally Regarded as Safe) additive by the FDA and approved as a food additive by several regulatory bodies worldwide, including the European Union and Brazil. In other words, numerous regulatory bodies worldwide consider it safe for both industrial use and human consumption. Its only recognized adverse effect is a laxative effect, which occurs when consumption exceeds 60 grams daily.
Xylitol and cardiovascular complications
A recent study published by the European Society of Cardiology aimed to investigate whether xylitol consumption is linked to an increased risk of cardiovascular events.
An initial observational “discovery” study analyzed 1,157 plasma samples to identify metabolites, the products of our metabolism, whose concentrations were associated with adverse cardiovascular events over a 3-year follow-up period.
Among the general characteristics of the participants for this study:
- All were registered with Genebank between 2001-2003.
- The average age was 65 years.
- Most participants were male (64%).
- The average BMI was 28.4, indicative of overweight.
- There was a high prevalence of cardiovascular disease (76%), coronary artery disease (76%), myocardial infarction (46%), and hypertension (72%).
Xylitol and its isomers [1] were found to be present at elevated levels in subjects who experienced a major adverse cardiovascular event (MACE) during the 3-year follow-up period, compared to those who did not.
A second study, involving other members of the same cohort, was performed to validate the findings made in “discovery,” this time involving 2,148 plasma samples.
Once again, it was observed that volunteers who experienced MACE had elevated levels of xylitol. More concerning, analysis using the Cox proportional hazards model [2] revealed that subjects with higher plasma levels of xylitol faced a 57% higher risk of incident MACE than those with lower plasma xylitol levels.
Searching for a Cause
The researchers presented studies in humans and mice to identify the underlying mechanism for Xylitol’s apparent harm.
In the human trial, ten healthy volunteers, aged over 18 years, who had not used antiplatelet medications in the past 14 days, antibiotics or probiotics in the last month, and did not have any illnesses that could affect the experiment's results, such as chronic gastrointestinal disorders or diabetes mellitus, were selected.
Blood samples were collected to measure xylitol levels before the intervention, a drink artificially sweetened with 30 g of xylitol dissolved in water, and instructed to consume it within a maximum of 2 minutes. Blood was again sampled over several intervals, platelet-rich plasma [3] was isolated from the blood collected, and platelet aggregation tests were conducted.
- The initial low plasma levels of xylitol rose a thousand-fold over the first 30 minutes after ingestion, returning to near normal 4 to 6 hours later.
- In the interval, several functional measurements of platelet responsiveness found a potential association between elevated xylitol levels and enhanced platelet aggregation.
In an animal model, mice underwent an injury to their carotid artery, the control group receiving an infusion of saline, while the second group received an infusion of xylitol. As a result, mice in the intervention group exhibited:
- A significant increase in clot formation.
- A considerable reduction in the time until blood flow stopped after the injury.
Based on these findings, the authors conclude that xylitol is associated with an increased risk of MACE and platelet reactivity with a potential for thrombosis in vivo.
Not So Fast
Before categorizing xylitol as a detrimental sweetener, it is essential to note the study's significant limitations. The “discovery” and “validation” studies are observational and cannot eliminate confounding variables or establish causality; at most, they can only establish correlations between a factor and an outcome.
Two well-recognized confounders were not counted, and no adjustments were made. There was no information available on the participants' physical activity. It is possible that a significant portion of the sample consisted of sedentary individuals, but since this information was not examined, we will never know.
More concerning, no dietary information was collected, making it impossible to assess the quality of the diet, specific foods consumed, and, most importantly, the amount of xylitol ingested. This raises a new question: if the quantity of xylitol consumed was not analyzed, and the authors observed that participants with the highest circulating levels of xylitol were at greater risk of MACE, how can we attribute this increase to exogenous xylitol consumption?
We cannot.
A more plausible explanation for this outcome, acknowledged by the researchers, could be that the observed levels result from endogenous production of xylitol rather than its consumption. This suggests that scenarios involving oxidative stress and other metabolic issues may increase this production, similar to erythritol.
Finally, it’s important to recall that most volunteers had a high burden of cardiovascular disease risk factors.
However, I must acknowledge that the clinical trial investigating platelet responsiveness has raised some intriguing hypotheses. If replicated and confirmed, these results could provide a slightly more solid foundation for understanding how xylitol behaves in the body and its potential adverse effects
Are we witnessing another case of an unwarranted “causation” involving xylitol consumption, similar to errors made by these authors in the erythritol studies?
For now, I agree with this quote from Dr. David Ludwig, a pediatric endocrinologist at Harvard’s Boston’s Childrens Hospital, who was not one of the study’s authors.
“It’s possible that xylitol carries some risks compared to consuming nothing, but these risks are smaller than if you were to consume similar amounts of sugar.”
Considering that xylitol is used as a direct substitute for sugar, an ingredient with extensive literature indicating that excessive consumption can lead to harmful health issues, I believe it offers a healthier option, a form of harm reduction, when consumed in moderation—like everything in life.
[1] Isomers are molecules sharing the same molecular formula but with different structural arrangements.
[2] Cox proportional hazards analysis is a statistical tool assessing how a covariate accelerates or decelerates the hazard function.
[3] Platelet-rich plasma has 2 to 7 times more platelets than are normally circulating in our blood.
Sources: Xylitol is prothrombotic and associated with cardiovascular risk. European Heart Journal. DOI: 10.1093/eurheartj/ehae244
Mammalian metabolism of erythritol: a predictive biomarker of metabolic dysfunction. Curr Opin Clin Nutr Metab Care. DOI: 10.1097/MCO.0000000000000665.
Is the Sugar Substitute Xylitol Safe for Your Heart?The New York Times
