Zero-Cal Erythritol Sweetener Disappoints on Cardiovascular Safety

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

Targeted metabolomic analyzes showed an approximate doubling of the risk of major adverse cardiovascular events (MACE) in individuals with the highest plasma erythritol levels in two independent validation cohorts, one in the US (fourth vs first quartile : adjusted RR 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, endocrinologist at the Cleveland Clinic, and colleagues.

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

“After exposure to dietary erythritol, a prolonged period of potentially increased thrombotic risk may occur. This is of concern given that the very subjects for which artificial sweeteners are marketed (patients with diabetes, obesity, of CVD and kidney failure) are those generally at greater risk of future cardiovascular events,” Hazen and his team wrote in natural medicine.

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

“Upon ingestion, erythritol is poorly metabolized and primarily excreted in the urine. Therefore, erythritol is characterized as both a ‘zero calorie’ or ‘non-nutritive’ sweetener and a ‘natural’ sweetener. “, driving its growing popularity and predicted to double its market share in the sweetener industry over the next 5 years,” Hazen Group noted.

The FDA classifies erythritol as “generally recognized as safe,” since it has not been associated with short-term insulin or glycemic effects, even in patients with impaired glycemic control or obesity. Thus, food labels are not required to disclose the amount of erythritol added to foods.

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

“The current results highlight the need for establishing reporting requirements, safety profiles, and daily intake amount margins as general consumption continues to increase,” Hazen and colleagues wrote.

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

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

For the present study, researchers had first identified erythritol as a molecule of concern after performing untargeted metabolomics studies in a discovery cohort comprising stable sequential 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 in the discovery (n=1157) and US (n=2149) and European (n=833) validation cohorts.

Hazen and colleagues acknowledged that erythritol was assessed only 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 to the general population.