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Though marketed as a healthy artificial sweetener, erythritol was still associated with cardiovascular disease (CVD) in various observational studies.

Targeted metabolomics analyses showed an approximate doubling of risk for major adverse cardiovascular events (MACE) among people with the highest plasma levels of erythritol in two independent validation cohorts, one in the U.S. (fourth vs first quartile: adjusted HR 1.80, 95% CI 1.18-2.77) and the other in Europe (adjusted HR 2.21, 95% CI 1.20-4.07), reported Stanley Hazen, MD, PhD, an endocrinologist at the Cleveland Clinic, and colleagues.

In a separate pilot intervention study in eight healthy volunteers, the researchers also found that drinking a erythritol-sweetened drink increased plasma erythritol to levels that were -- for several days -- well above thresholds associated with heightened platelet reactivity and thrombosis potential.

"Following exposure to dietary erythritol, a prolonged period of potentially heightened thrombotic risk may occur. This is of concern given that the very subjects for whom artificial sweeteners are marketed (patients with diabetes, obesity, history of CVD and impaired kidney function) are those typically at higher risk for future CVD events," Hazen and team wrote in .

Erythritol is endogenously produced in humans by the pentose phosphate pathway. It may also be ingested as a naturally occurring substance in fruits and vegetables, or as a sugar substitute added in large amounts to processed foods. The latter is increasingly common for many people.

"Upon ingestion, erythritol is poorly metabolized and mostly excreted in the urine. Consequently, erythritol is characterized as both a 'zero-calorie' or 'non-nutritive' sweetener and a 'natural' sweetener, leading to its rapidly rising popularity and predicted doubling in market share within the sweetener sector in the next 5 years," Hazen's group noted.

The FDA classifies erythritol as since it has not been associated with short-term insulinemic or glycemic effects, even for patients with impaired glucose control or obesity. As such, food labels are not required to disclose how much erythritol has been added to foods.

However, caution regarding the long-term safety of erythritol is warranted based on the latest data.

"The present results highlight the need to establish reporting requirements, safety profiles and margins of daily intake amounts given that broad consumption continues to increase," Hazen and colleagues wrote.

More broadly, the literature is lacking in data on cardiovascular risks of consuming artificial sweeteners in general. Randomized clinical trials examining their long-term safety have not been performed, even for earlier adopted forms such as aspartame and sucralose, the authors said.

From what has been reported, they added, there is some evidence linking the artificial sweeteners to adverse cardiometabolic phenotypes, such as weight gain, insulin resistance, type 2 diabetes, and CVD, including atherothrombotic complications and cardiovascular mortality. Cancer has also emerged as a risk of ingesting artificial sweeteners.

For the present study, the investigators had first identified erythritol as a molecule of concern after performing untargeted metabolomics studies in a discovery cohort comprising sequential stable patients undergoing elective diagnostic cardiac evaluation with 3-year longitudinal data on MACE (i.e., death, myocardial infarction, and stroke).

Treated as a continuous variable, plasma erythritol level was independently associated with MACE across the discovery (n=1,157) and the U.S. (n=2,149) and European (n=833) validation cohorts.

Hazen and colleagues acknowledged that erythritol was assessed just once as an overnight fasting level at the time of enrollment, with no serial measurements available. Another limitation was that the cohort had been recruited from quaternary referral centers and may have a higher prevalence of cardiovascular disease and traditional risk factors compared with the general population.

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