Artificial Sweetener in Keto-Related Foods Tied to CV Risk

A multi-part study reports that erythritol — a sugar alcohol (polyol) increasingly used as an artificial sweetener that is also made in the body — is associated with risk of major adverse cardiovascular events (MACE) and promotes clotting (thrombosis).

Erythritol is one of the most widely used artificial sweeteners with rapidly increasing prevalence in processed and "keto-related" foods. Artificial sweeteners are "generally recognized as safe" (GRAS) by the US Food and Drug Administration, so there is no requirement for long-term safety studies, and little is known about the long-term health effects.

The current research, published online February 27 in Nature Medicine by Marco Witkowski, MD, and colleagues, had multiple parts.

First, in a group of patients undergoing cardiac risk assessment, the researchers found that high levels of polyols, especially erythritol, were associated with increased 3-year risk of MACE, defined as cardiovascular death or nonfatal myocardial infarction (MI) or stroke.

Next, the association of erythritol with this outcome was reproduced in two large US and European groups of stable patients undergoing elective cardiac evaluation.

Next, adding erythritol to whole blood or platelets led to clot activation. And lastly, in eight healthy volunteers, ingesting 30 g of an erythritol-sweetened drink — comparable to a single can of commercially available beverage or a pint of keto ice cream — induced marked and sustained (> 2 day) increases in levels of plasma 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 senior author Stanley L. Hazen, MD, PhD.

"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," Hazen, co-section head of Preventive Cardiology at Cleveland Clinic, Ohio, said in a press release from his institution.

"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. 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," Hazen urged.

The topic remains controversial.

Duane Mellor, PhD, a registered dietitian and senior teaching fellow at Aston University, Birmingham, UK, told the UK Science Media Centre: "This paper effectively shows multiple pieces of a jigsaw exploring the effects of erythritol — although it claims to show an associated risk with the use of erythritol as an artificial sweetener and cardiovascular disease, I believe it fails to do so, as ultimately, erythritol can be made inside our bodies and the intake in most people's diet is much lower than the amount given in this study."

Hazen countered that data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) in the US show that, in some individuals, daily intake of erythritol is estimated to reach 30 g/day.

"Many try and reduce sugar intake by taking many teaspoons of erythritol in their tea, coffee, etc, instead of sugar," Hazen added. "Or they eat keto processed foods that have significant quantities of erythritol within it."

"These studies are a warning for how our processed food (keto and zero sugar, especially) may inadvertently be causing risk/harm...in the very subset of subjects who are most vulnerable," according to Hazen.

Erythritol Marketed as 'Zero Calorie', 'Non-nutritive', or 'Natural'

Patients with type 2 diabetes and obesity are often advised to replace sugar with artificial sweeteners for better glucose control and weight loss, but growing epidemiologic evidence links artificial sweetener consumption with weight gain, insulin resistance, type 2 diabetes, and cardiovascular disease, the researchers write.

Erythritol is naturally present in low amounts in fruits and vegetables; the artificial sweetener erythritol that is produced from corn is only 70% as sweet as sugar.

Upon ingestion it is poorly metabolized, and most is excreted in the urine, so it is characterized as a "zero calorie", "non-nutritive," or "natural sweetener." It is predicted to double in marketshare in the sweetener sector in the next 5 years.

Multi-Part Study

In the first part of their study, in a discovery cohort in 1157 patients undergoing cardiovascular assessment with 3-year outcomes, the researchers identified polyols that were associated with MACE, and erythritol was among the top MACE-associated molecules.

Next, in a US validation cohort of 2149 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 1.8-fold higher risk of MACE than patients in the lowest quartile (P = .007), after adjusting for cardiovascular risk factors.

In a European validation cohort of 833 patients, over a 3-year follow-up, patients with plasma levels of erythritol in the highest quartile had a 2.21-fold higher risk of MACE than patients in the lowest quartile (P = .010, after adjustment).

At physiologic levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo.

Finally, in a prospective pilot intervention study, erythritol ingestion in healthy volunteers induced marked and sustained increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies.

Others Weigh In

"While I think the finding certainly warrants further investigation, don't throw out your sweeteners just yet," Oliver Jones, PhD, professor of chemistry, RMIT University, Melbourne, Australia, commented.

"This study only looks at erythritol, and artificial sweeteners are generally considered safe. Any possible (and, as yet unproven) risks of excess erythritol would also need to be balanced against the very real health risks of excess glucose consumption," he said.

Hazen responded: "True enough. Erythritol is but one of many artificial sweeteners. That is why it is important to read labels. This study can make patients be informed about how to potentially avoid something that might cause them inadvertent harm."

"The key findings of this study are that high blood levels of erythritol are strongly associated with cardiovascular outcomes in high-risk patients, which has been replicated in separate validation studies," said Tom Sanders, DSc, PhD, professor emeritus of Nutrition and Dietetics, King's College London.

"Diabetes UK currently advises diabetes patients not to use polyols," he added.

Hazen noted that "About three quarters of the participants had coronary disease, high blood pressure, and about a fifth had diabetes."

The researchers acknowledge, however, that the observational studies cannot show cause and effect.

The study was supported by the Office of Dietary Supplements at the National Institutes of Health, the Leducq Foundation, and the German Research Foundation (Deutsche Forschungsgemeinschaft). Mellor, Jones, and Sanders have reported no relevant financial relationships. Disclosures for all study authors are listed with the article.

Nat Med Abstract. Published online February 27, 2023.

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