A new study has lent more support to previous epidemiological data that ties the popular sugar substitute erythritol to elevated cardiovascular risk [1].
Deceptively sweet
Sugar substitutes have been around for decades, and while some people have reported deceases in weight and blood glucose, a growing body of research suggests there might be some downsides to guiltless sweetness.
Recent epidemiological studies have found a link between the popular sweetener erythritol and increased cardiovascular and cerebrovascular risk. A study from 2023 showed that elevated erythritol levels were positively associated with non-fatal and fatal heart disease and stroke, both in males and females, across several population subgroups in the United States and Europe [2].
Populational studies can neither establish a causal relationship nor provide a mechanistic explanation. However, in this case, the researchers also conducted a small prospective trial showing that exposure to an equivalent of 30 grams of erythritol, the usual dose found in one standard-size artificially sweetened drink, significantly increases clot-forming (thrombogenic) potential both in vitro and in vivo. A new study from the University of Colorado Boulder, published in the Journal of Applied Physiology, went even further, revealing a possible mechanism behind this association.
Multiple signs of cardiovascular dysfunction
The researchers worked on an in vitro model based on brain microvascular endothelial cells. These cells line capillaries in the brain and are important for maintaining healthy blood flow, blood-brain barrier integrity, and low inflammation levels. “Endothelial cell dysfunction is a major antecedent to heart disease and stroke,” the authors wrote, “however, the effects of erythritol on endothelial cell function are not well understood.”
After subjecting the cells to the same dose of erythritol as in the earlier 2023 study for 24 hours, the researchers found that the levels of reactive oxygen species (ROS), harmful molecules that can oxidize and damage DNA, proteins, and lipids, accelerating aging and disease processes, was 75% higher than in control cells.
Expression of catalase and SOD-1 was 25% and 45% higher, respectively. Catalase is an antioxidant enzyme that breaks hydrogen peroxide down into water and oxygen, and SOD-1 converts superoxide radicals into less-reactive hydrogen peroxide. Together, they form a frontline enzymatic shield against oxidative stress, which the cells apparently used with limited success, to mitigate the increased levels of ROS.
According to the paper, these results suggest that, at minimum, erythritol does not negatively affect cells’ antioxidant machinery. “However,” the authors note, “we cannot rule out the possibility that longer exposure or repeated chronic exposure to erythritol would result in diminished SOD-1 and catalase bioavailability and in further exacerbation of ROS production.”
The researchers then assessed the production of nitric oxide (NO), a compound that relaxes blood vessel walls, curbs platelet sticking, and dampens inflammation to preserve healthy vascular tone and endothelial function. They found changes in phosphorylation, a type of post-translational modification, of eNOS, an enzyme central to NO production, which ultimately resulted in a 20% decrease in NO production. Diminished NO bioavailability is a hallmark of endothelial dysfunction and is linked to elevated cardiovascular risk [3].
Another worrying sign was that erythritol treatment caused a 30% increase in endothelin-1, a peptide that constricts blood vessels, elevates blood pressure, and fosters vascular inflammation. Along with lower NO availability, this can eventually lead to disrupted blood flow and increased risk of stroke.
Lastly, the researchers assessed the levels of t-PA, the enzyme that transforms plasminogen, an inactive blood protein, into plasmin, the active form that chews through fibrin and melts clots. Baseline t-PA levels were identical in the treated and control cells. However, erythritol blunted the increase in t-PA in response to thrombin, which is how an endothelial cell reacts to clotting risk.
Approach with caution
The researchers admit that in vivo studies are needed to confirm their findings. However, this is already an important addition to the current epidemiological data that points to potential cardiovascular risks from artificial sweeteners.
“While erythritol is widely used in sugar-free products marketed as healthier alternatives, more research is needed to fully understand its impact on vascular health,” said Auburn Berry, a graduate student at the University of Colorado Boulder and first author of the study. “In general, people should be conscious of the amount of erythritol they are consuming on a daily basis.”
Literature
[1] Berry, A. R., Ruzzene, S. T., Ostrander, E. I., Wegerson, K. N., Fersiva, N. O., Stone, M. F., … & DeSouza, C. A. (2025). The Non-Nutritive Sweetner Erythritol Adversely Affects Brain Microvascular Endothelial Cell Function. Journal of Applied Physiology.
[2] Witkowski, M., Nemet, I., Alamri, H., Wilcox, J., Gupta, N., Nimer, N., … & Hazen, S. L. (2023). The artificial sweetener erythritol and cardiovascular event risk. Nature medicine, 29(3), 710-718.
[3] Yetik-Anacak, G., & Catravas, J. D. (2006). Nitric oxide and the endothelium: history and impact on cardiovascular disease. Vascular pharmacology, 45(5), 268-276.
