Erythritol, a popular sugar alcohol and low-calorie sweetener, is widely used in various beverages, baked goods, sauces, candies, and other products. However, a recent study published in “Nature Medicine” has raised concerns about its potential impact on health. The study revealed that erythritol might lead to thrombosis, the formation of blood clots, and is associated with an increased risk of major adverse cardiovascular events (MACE), including myocardial infarction and stroke. As a result, the researchers emphasized the importance of conducting a comprehensive assessment of the long-term safety of erythritol [1].
This study was carried out by a team from the renowned Cleveland Clinic. Prior to the publication of this research, several studies indicated that erythritol had a neutral effect on health and was considered superior to other artificial sweeteners, mainly because our gut microbiota cannot ferment erythritol.
Unfortunately, this study may have inadvertently led readers to an unwarranted conclusion that increased consumption of erythritol could elevate the risk of cardiovascular diseases. It is crucial to approach such findings with caution and consider various factors before drawing definitive conclusions.
The Study Design
Let’s delve into the research conducted by the Cleveland team. They performed four different yet interconnected studies:
Firstly, they conducted an untargeted screening of blood samples from over 1157 individuals to identify any metabolites that might be associated with the risk of cardiovascular disease. Among the candidates, erythritol emerged as a “suspect” with higher levels in the blood showing a correlation with MACE (Major Adverse Cardiovascular Events).
Next, they analyzed samples from two epidemiological studies, one from Europe and the other from the United States, and found a significant correlation between higher erythritol levels in the blood and an increased risk of cardiovascular events.
They proceeded to conduct in vitro experiments, where erythritol was added to blood samples, and they observed an accelerated clotting rate, indicating an increased risk of thrombosis. Thrombosis serves as a risk factor for adverse cardiovascular events, particularly during vascular injuries.
Finally, an intervention study was carried out, where participants were given a safe dose (30g) of erythritol. The study revealed that erythritol persisted in the participants’ bodies for over 3 days. Based on the data from the in vitro experiments, the concentration of erythritol in the blood reached a level capable of increasing the risk of blood clot formation. Consequently, it was inferred that after consuming a safe dose of erythritol, the concentration of erythritol in the blood would be sufficient to raise the risk of blood clots and, consequently, increase the risk of cardiovascular events.
Lack of Food Intake Data
By this point, some of you may have already noticed the logical flaws in the aforementioned studies. The research paper did not provide dietary data for the analyzed population samples from the two epidemiological studies in Europe and the United States. Specifically, it did not clarify whether the levels of erythritol in their blood were derived from dietary intake or due to endogenous metabolism or other dietary and lifestyle factors (confounding factors). In fact, even before the widespread use of erythritol, at least two large-scale epidemiological studies had already found a correlation between erythritol levels in the human body and diabetes and cardiovascular diseases [2][3]. This suggests that the blood erythritol in these individuals was unlikely derived solely from dietary intake of erythritol itself.
One of the epidemiological studies analyzed in the current research (US cohort) was conducted before erythritol became a food additive and sweetener, which means it had no direct relevance to erythritol ingestion. This particular sample precisely illustrates that factors other than direct intake of erythritol through processed foods or beverages can lead to elevated erythritol levels in the blood. On the other hand, the data from another sample collected between 2016-2018 (patients of Charité University Hospital in Europe) should have included both endogenous and dietary sources of erythritol. However, as erythritol only gained popularity several years ago, it remains unclear how much of the erythritol in the blood of this sample population came from direct dietary intake.
Furthermore, the authors themselves acknowledge that previous experiments have shown human red blood cells can endogenously produce erythritol through the pentose phosphate pathway [4][5]. Additionally, a study from 2017 found a positive correlation between obesity and erythritol levels in the blood. Isotopically labeled glucose was metabolically converted into more erythritol in the blood of obese patients. This raises the question of whether erythritol from the diet is genuinely associated with cardiovascular events or if it is merely a marker related to obesity, which is itself linked to cardiovascular disease. In fact, obese people, who are at a higher risk of CVD, may consume more exogenous erythritol and also generate more endogenous erythritol.
Higher Clotting Rate Not necessarily Implying an Increased Risk of CVD
Another logical flaw in this study is its exaggerated association between a higher rate of blood clotting and cardiovascular events. While it’s true that an increased clotting rate raises the risk of thrombosis, which in turn can lead to cardiovascular events, it’s crucial to consider that an elevated clot formation rate typically occurs only after vascular injury. If your blood vessels are healthy and elastic without issues like atherosclerosis, clot formation rate is not a concern. Additionally, people with vitamin K deficiency and impaired liver function may be unable to form clots, which also increases the risk of cardiovascular disease. Thus, we cannot conclusively determine if a higher clotting rate is inherently good or bad without context.
Cardiovascular events are linked to factors like hypertension, high triglycerides, high LDL cholesterol, and low HDL cholesterol. Although these cardiovascular-related data are present in the two cohort studies, the paper’s authors seem to have overlooked them. They solely focused on the association between erythritol levels and one risk factor, blood clotting rate, without adjusting for other confounding factors (e.g., hypertension, dyslipidemia, hyperglycemia). This introduces a significant reporting bias and may lead to misleading conclusions.
In the animal experiments and in vitro cell experiments conducted by the Cornell University team in 2022, they discovered a direct increase in endogenous erythritol levels due to high blood sugar and oxidative stress. Notably, high blood sugar and oxidative stress are fundamental components of the pathophysiological mechanisms of cardiovascular diseases, not mere associations [6] [7]. Considering this, at this point, erythritol from dietary source should perhaps not held guilty anymore. While we can continue to investigate its role, there is currently no direct evidence to “prosecute” it as the mastermind behind cardiovascular diseases.
From an academic standpoint, this study lacks “internal validity,” as it has intertwined different factors that confound the findings. It is puzzling why they conducted an in vitro mechanistic study (demonstrating erythritol increasing clot formation rate) and a human intervention study when one of the cohort studies showed no correlation with erythritol intake. These aspects of the study seem entirely unnecessary.
A more appropriate approach would likely be a long-term controlled prospective study, comparing cardiovascular disease patients who consume varying amounts of erythritol while adjusting for other confounding factors (e.g., hyperglycemia, dyslipidemia, hypertension, differences in LDL and HDL cholesterol, triglycerides, etc.). Such a study would provide better insights into whether dietary erythritol may be associated with an increased risk of MACE. For now, even though the research team did not explicitly state it in their conclusion, it is evident that they have been led to an unwarranted conclusion: that consuming erythritol increases the risk of cardiovascular diseases.
Summary
I’m not really a fan of erythritol, as I feel like we don’t have enough understanding about how artificial sweeteners or sugar alcohols affect our gut microbiota and overall health.
But let’s not jump the gun and start blowing the whistle on erythritol’s potential risks for cardiovascular disease just yet. We need more research and data before we draw any conclusions. So, for now, it’s best to keep an eye out and stay informed!
References:
[1] Witkowski, M. et al. (2023). The artificial sweetener erythritol and cardiovascular event risk. Nature medicine, 10.1038/s41591-023-02223-9. Advance online publication. https://doi.org/10.1038/s41591-023-02223-9
[4] Hootman, K. C. et al. (2017). Erythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults. Proceedings of the National Academy of Sciences of the United States of America, 114(21), E4233–E4240. https://doi.org/10.1073/pnas.1620079114
