Erythritol, a 4-carbon sugar alcohol (a polyol) commonly used as a sugar substitute, was linked to significant risk of heart attack and stroke, according to a study from researchers at the Cleveland Clinic. Results were published in Nature Medicine and received substantial attention in mainstream media outlets, including USA Today, the New York Times, CNN, and others. 

Researchers studied more than 4,000 people in the U.S. and Europe, concluding those with higher blood concentrations of erythritol were at a higher risk of experiencing a major adverse cardiac event such as heart attack, stroke or death.

“Sweeteners like erythritol have rapidly increased in popularity in recent years but there needs to be more in-depth research into their long-term effects,” Stanley Hazen, MD, PhD, chairman for the Department of Cardiovascular and Metabolic Sciences in Lerner Research Institute and co-section head of preventive cardiology at Cleveland Clinic, said in a statement. “Cardiovascular disease builds over time, and heart disease is the leading cause of death globally. We need to make sure the foods we eat aren’t hidden contributors.” 

Alternative sweeteners are common replacements in low-sugar products, which are recommended for people who have obesity, diabetes, or metabolic syndrome. However, people with these conditions, which already place them at higher risk for heart attack and stroke, were most significantly impacted by the risk associated with erythritol.

“Our study shows that when participants consumed an artificially sweetened beverage with an amount of erythritol found in many processed foods, markedly elevated levels in the blood are observed for days—levels well above those observed to enhance clotting risks,” said Hazen. “It is important that further safety studies are conducted to examine the long-term effects of artificial sweeteners in general, and erythritol specifically, on risks for heart attack and stroke, particularly in people at higher risk for cardiovascular disease.”

Details

In the study, the researchers initially conducted an untargeted metabolomics analysis in patients undergoing cardiac risk assessment (1,157 patients). Circulating levels of multiple polyol sweeteners, especially erythritol, were associated with an incident (3 year) risk for major adverse cardiovascular events (MACE).

Subsequent targeted metabolomics analyses in independent U.S. (n = 2,149) and European (n = 833) validation cohorts of stable patients undergoing elective cardiac evaluation confirmed this association, researchers said.

At physiological levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo. Finally, in a prospective pilot intervention study, erythritol ingestion in healthy volunteers (n = 8) induced marked and sustained (>2 d) increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential.

Researchers said these findings reveal that erythritol is both associated with incident MACE risk and fosters enhanced thrombosis. As such, studies assessing the long-term safety of erythritol are warranted.

Implications

Upon ingestion, erythritol is poorly metabolized and mostly excreted in the urine, researchers wrote. “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.”

As the study authors noted, while both the European Union and the U.S. Food and Drug Administration (FDA) generally recognize erythritol as safe, erythritol’s safety has been assessed only by short-term animal toxicity studies, and human clinical studies which ended after a duration of four weeks. While it occurs endogenously in human tissues and food, it is at levels 1,000-fold lower than when it is used as an additive to processed foods.

“The general lack of reporting of erythritol in the literature might be due in part to difficulties in quantification of erythritol, like other polyols, due to its structural isomers,” the authors wrote. “The present studies suggest that following ingestion of an artificially sweetened food harboring typical levels of erythritol as artificial sweetener, plasma levels of erythritol remain elevated for many days, well above the thresholds necessary to enhance stimulus-dependent platelet reactivity, even among healthy volunteers.”

Further studies are needed to establish the impact of elevated erythritol levels in subjects, especially those who have impaired renal function or cardiovascular disease.

“Our study shows that when participants consumed an artificially sweetened beverage with an amount of erythritol found in many processed foods, markedly elevated levels in the blood are observed for days—levels well above those observed to enhance clotting risks,” Hazen said in a statement. “It is important that further safety studies are conducted to examine the long-term effects of artificial sweeteners in general, and erythritol specifically, on risks for heart attack and stroke, particularly in people at higher risk for cardiovascular disease.”

The study was partially funded by the National Heart, Lung, and Blood Institute and the Office of Dietary Supplements, both of the National Institutes of Health (NIH).