Evidence Mounts That Sugar Substitute Erythritol Raises Cardiovascular Risk

Ingesting the non-nutritive sweetener erythritol — at a dose typically contained in a “sugarless” soda or muffin — rapidly enhances platelet reactivity in human blood and thereby increases thrombosis potential. This finding, from a new intervention study in healthy volunteers, adds to increasing evidence that this sugar alcohol may not be as safe as currently classified by food regulatory agencies and should be reevaluated as an ingredient.

The study, reported in Arteriosclerosis, Thrombosis and Vascular Biology, was conducted by a team of Cleveland Clinic researchers as part of a series of investigations on the physiological effects of commonly consumed sugar substitutes.

“Many professional societies and clinicians routinely recommend that people at high cardiovascular risk — those with obesity, diabetes or metabolic syndrome — consume foods that contain sugar substitutes rather than sugar,” says senior and corresponding author Stanley Hazen, MD, PhD, Chair of Cardiovascular and Metabolic Sciences in Cleveland Clinic Lerner Research Institute and Co-Section Head of Preventive Cardiology. “It is incumbent upon us to ensure that we are not unwittingly provoking adverse events with this advice.”

Non-nutritive sweeteners face increasing scrutiny

Erythritol is classified by the U.S. FDA and the European Food Safety Authority as a GRAS (“generally recognized as safe”) ingredient, allowing its use without restriction in food products. This is primarily because it is a sugar alcohol found naturally in fruits and vegetables and a byproduct of glucose metabolism in human tissue, albeit in very small quantities.

Many people consume processed foods and beverages with erythritol added as a sweetener because they believe these products are healthier than sodas or baked goods containing sugar. However, observational cohort studies, as well as recent mechanistic investigations by Dr. Hazen’s group, have detected signals that erythritol in typically consumed amounts may increase cardiovascular risk.

The group’s previous diverse human and animal investigations of erythritol were published in Nature Medicine (2023;29:710-718) and revealed the following:

• At-risk cardiac patients with high plasma erythritol levels were about twice as likely to have a major cardiac event over the next three years compared with similar patients with low erythritol levels.
• Adding erythritol to blood products in vitro to achieve concentrations seen in patients led to increased platelet aggregation and adhesion.
• Increasing circulating erythritol levels in a murine model of arterial injury led to a faster rate of clot formation.

“All indicators suggested that higher erythritol levels increase thrombosis risk,” summarizes Dr. Hazen, who led the research.

New intervention study: Design and results

The current prospective intervention study was designed to more directly observe the effects on platelets in humans following erythritol ingestion. After blood was drawn following an overnight fast, 20 healthy volunteers consumed water mixed with either 30 g erythritol (comparable to the dose in an artificially sweetened soda or baked good) or 30 g of glucose (n = 10 per group; mean age of 30 years in each group). Blood was drawn again after 30 minutes, and plasma levels of erythritol were assessed, as were multiple indicators of platelet function (i.e., analyses by aggregometry with different agonists and quantification of alpha and dense granule marker release).

Key findings included the following:

• Postprandial mean erythritol level increased more than 1,000-fold in the erythritol group compared with baseline (from 4 µM to 6,480 µM, P < .0001).
• Circulating erythritol levels remained similar before and after glucose consumption, and mean glucose level modestly increased (from 87 to 127 mg/dL, P = .002).
• Measures of platelet aggregation showed a striking increase following erythritol ingestion (P < .0001 for each subject and agonist examined) but did not change after glucose consumption.
• Measures of platelet dense granule (serotonin) and alpha granule (CXCL4) release showed significant increases following erythritol ingestion (P < .05 for each subject and agonist examined) but did not change after glucose consumption.

Findings merit reevaluation of sugar alcohols

“This research raises some concerns that a standard serving of an erythritol-sweetened food or beverage may acutely stimulate a direct prothrombotic effect,” says study co-author W. H. Wilson Tang, MD, Research Director for Heart Failure and Cardiac Transplantation Medicine at Cleveland Clinic. “Erythritol and other sugar alcohols commonly used as sugar substitutes should be evaluated for potential long-term health effects, especially when such effects are not seen with glucose itself.”

He adds that the results of this erythritol intervention study are especially notable because they come on the heels of another study by this research group showing that ingestion of a solution containing 30 g of xylitol — another sugar alcohol used to sweeten food and beverages — produced similar increases in plasma levels and similar acute effects on platelet aggregation in healthy volunteers (Eur Heart J. Epub 2024 Jun 6). Similar to current evidence with erythritol, the investigations with xylitol also included large-scale clinical observation studies showing that elevation in plasma xylitol levels is associated with increased risk for heart attack, stroke or death over three years of follow-up.

Drs. Tang and Hazen urge that further prospective clinical studies be conducted to test the cardiovascular safety of these sugar alcohols when used as sugar substitutes, considering their widespread consumption by high-risk individuals. In the meantime, they urge their patients to completely avoid highly processed “sugar free” foods.

“I feel that choosing sugar-sweetened treats occasionally and in small amounts would be preferable to consuming drinks and foods sweetened with these sugar alcohols, especially for people at elevated risk of thrombosis, such as those with heart disease, diabetes or metabolic syndrome,” Dr. Hazen advises.