Sugar Substitute Erythritol Linked to Increased Cardiovascular Risk

Erythritol — a commonly used artificial sweetener in processed foods — is associated with heightened risk of major adverse cardiovascular events (MACE), independent of traditional risk factors for cardiovascular disease. So found an international team of investigators using U.S. and European cohorts, in addition to conducting in vitro studies on platelet activity using erythritol and animal model studies with erythritol at commonly ingested levels. The research was published in Nature Medicine.

“Since sugar substitutes are often consumed at high levels, especially by people with obesity and diabetes, it is critical to ensure that they do not increase cardiovascular risk,” says the study’s senior and corresponding author, Stanley Hazen, MD, PhD, Chair of the Department of Cardiovascular and Metabolic Sciences in Cleveland Clinic’s Lerner Research Institute. “Artificially sweetened products are actually recommended by some professional societies for those who are most vulnerable to their potential ill effects.”

Erythritol: considered safe, but is it?

Erythritol is a common additive used to sweeten as well as improve the taste and so-called mouthfeel of other artificial sweeteners. Because it is produced endogenously in human tissue and is present in fruits and vegetables, it is considered to be a “generally regarded as safe” (GRAS) ingredient by the U.S. FDA and the European Union, and its content need not be disclosed on food labels. However, common foods and drinks — such as artificially sweetened bakery products, “keto” products and many “zero calorie” products — may contain erythritol. When they do, erythritol is typically used in amounts many thousands of times higher than natural levels.

While erythritol has undergone short-term toxicity tests (mainly evaluating mutagenicity) and human tolerance testing (to determine maximum levels ingested before acute adverse effects are observed), little is known about its possible long-term health effects. Epidemiological evidence has been mounting that associates the consumption of artificial sweeteners in general with weight gain, diabetes and cardiovascular mortality, but it is difficult to tease out bias from such data. Randomized clinical trials looking at long-term outcomes have not been performed.

Erythritol is a particularly worrisome ingredient, notes Dr. Hazen, who is also Co-Section Head of Preventive Cardiology at Cleveland Clinic. It is only about 70% as sweet as sugar, so it is used in large quantities to achieve desired sweetness. “A ‘diabetic’ confection or bakery item may contain as much as 50% erythritol by dry weight,” he remarks.

Study design and results

The researchers conducted a series of diverse investigations to discover compounds linked to residual cardiovascular disease risks (the risk that remains after accounting for traditional risk factors), and they discovered erythritol as a lead compound in that search. They then designed numerous studies to evaluate the impact of commonly consumed quantities of erythritol on cardiovascular disease-relevant phenotypes. The studies are summarized in brief below.

Initial untargeted metabolomics studies. This “discovery cohort” consisted of 1,157 patients undergoing cardiac assessment at Cleveland Clinic with at least three years of follow-up. Using untargeted mass spectrometry, the investigators identified compounds in these patients’ plasma that were associated with MACE, defined as death or nonfatal myocardial infarction or stroke over the three years following enrollment/sample collection. They found several artificial sweeteners to be associated with incident MACE risks, with erythritol being the most strongly predictive.

Targeted metabolomics analyses.Next came more thorough quantitative studies of erythritol using new cohorts of patients undergoing elective cardiac evaluation: one from Cleveland Clinic (n = 2,149) and one from Charité Hospital in Berlin, Germany (n = 833). Both of these quaternary referral centers cover large catchment areas, and patients had multiple cardiovascular risk factors. Findings included the following:

• Plasma erythritol levels were higher among those with high prevalent cardiovascular disease and risk factor burden (P < 0.0001, each cohort).
• High plasma levels of erythritol were associated with incident MACE over three years of follow-up (P < 0.0001, each cohort).
• After adjusting for cardiovascular risk factors, higher erythritol levels were associated with higher risk of MACE (adjusted hazard ratio for fourth vs. first quartile = 1.80 [95% CI, 1.18-2.77] in the U.S. cohort and 2.21 [95% CI, 1.20-4.07] in the European cohort).
• Associations between erythritol and MACE risk were found regardless of sex and presence of individual cardiovascular risk factors.

In vitro and ex vivo mechanistic studies in whole blood, platelet-rich plasma and isolated platelets from healthy volunteers. After adding erythritol to either whole blood, platelet-rich plasma or isolated platelets to achieve concentrations in the range observed among the previous cohorts, the researchers found that platelet aggregation and adhesion increased with increasing erythritol dose.

In vivo mechanistic studies using mice. In a murine model of arterial injury, increasing circulating erythritol levels across physiological levels led to faster rate of clot formation.

Erythritol ingestionstudies. Healthy volunteers (n = 8) were given an erythritol-sweetened drink (30 g erythritol), a load comparable to a single can of artificially sweetened beverage. Plasma erythritol levels increased 1,000-fold rapidly after ingestion. They remained elevated for more than two days at levels above the threshold that adversely affected platelet function in the mechanistic studies.

More research — and transparency — needed

This series of studies provides the strongest evidence to date of cardiovascular risk associated with an artificial sweetener. Dr. Hazen urges the following actions by food regulatory agencies:

• Require the food industry to conduct more safety studies of sugar substitutes, including long-term impacts and effects on cardiovascular disease.
• Reappraise food labeling requirements to better inform the public of ingredients.

“I tell my patients to stay away from artificial sweeteners and to instead modestly consume natural sweeteners, such as honey and sugar,” he adds.

Dr. Hazen’s group is continuing their research on artificial sweeteners and cardiovascular risk.

“Our findings, together with other recent publications, have brought caution around the widely held belief that replacing sugar with some artificial sweeteners can provide benefits over the known risks of excess sugar consumption,” says study co-author W.H. Wilson Tang, MD, Research Director for the Section of Heart Failure and Cardiac Transplantation at Cleveland Clinic. “More rigorous investigations and methodologies are clearly needed in this important area of public health.”

“Artificial sweeteners have previously been suspected to be associated with obesity, diabetes and heart disease,” adds Dennis Bruemmer, MD, PhD, Director of Cleveland Clinic’s Center for Cardiometabolic Health. “This well-performed study provides important confirmation of increased cardiovascular risk from a commonly used artificial sweetener and sheds light on the reason underlying this relationship. One would hope that the FDA will mandate disclosure to consumers of this increased cardiovascular risk associated with artificial sweetener use, to promote awareness and healthier food choices in the United States.”