New research from the US has found that that erythritol, a popular artificial sweetener, is associated with up to a 21% increased risk of death, heart attack and stroke.
The study from the Cleveland Clinic, published 27 February 2023 in Nature Medicine, involved over 4,000 people in the U.S. and Europe and found those with higher blood erythritol levels were at elevated risk of experiencing a major adverse cardiac event such as heart attack, stroke, or death.
They also examined the effects of adding erythritol to either whole blood or isolated platelets, revealing that erythritol made platelets easier to activate and form a clot, a finding confirmed by pre-clinical studies which showed that ingestion of erythritol heightened clot formation.
This is the first detailed examination of the relationship between erythritol and both CVD and atherothrombotic complications.
Senior author Dr Stanley Hazen, chairman for the Department of Cardiovascular & Metabolic Sciences at the Lerner Research Institute and co-section head of Preventive Cardiology at Cleveland Clinic said that with the growing worldwide obesity epidemic, artificial sweeteners are increasingly common ingredients in soft drinks, processed foods and even personal care products.
“In fact, artificial sweeteners have even been detected in ground and tap water,” Dr Hazen said.
“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 as heart disease is the leading cause of death globally, we need to make sure the foods we eat aren’t hidden contributors.”
Erythritol is a 4-carbon sugar alcohol (polyol) about 70% as sweet as sugar that is naturally found in low amounts in fruits and vegetables.
However, when it is incorporated into processed foods it is typically added at quantities 1,000-fold higher than endogenous levels and can makes up to 60% of the weight of some creams or pastry products.
“Because numerous ‘zero calorie’ or ‘keto’-friendly prepared foods and beverages can possess relatively large quantities of erythritol, we thought it would be of interest to assess the physiological range in circulating erythritol levels observed following a relevant dietary exposure,” Dr Hazen explained.
Products containing erythritol are often recommended for people who have obesity, diabetes or metabolic syndrome to improve glycaemic control and help achieve weight loss, yet people with these conditions are also at higher risk for adverse cardiovascular events.
There is also growing epidemiological evidence linking the consumption of artificial sweeteners to adverse cardiometabolic phenotypes such as weight gain, insulin resistance, type 2 diabetes and atherothrombotic complications, as well as CVD.
“After ingestion, erythritol is poorly metabolized by the body. Instead, it goes into the bloodstream and leaves the body mainly through urine,” Dr Hazen said.
“The human body creates low amounts of erythritol naturally, so any additional consumption can accumulate.”
He pointed out that randomized clinical trials examining the long-term safety of consuming artificial sweeteners have not been performed, even for more early adopted forms such as aspartame and sucralose.
“Indeed, despite the growing incorporation of artificial sweeteners into the food chain, their cardiovascular risks have seldom been investigated,” Dr Hazen said.
“Erythritol’s safety has been assessed by short-term animal toxicity studies and reported human clinical studies with ingestion up to 4 weeks.”
Based on these studies, along with its natural occurrence both endogenously in human tissues and in food (albeit at levels 1,000-fold lower than added to processed foods), erythritol is ‘generally recognized as safe’ by both the EU and the FDA, which means there is no requirement for long-term safety studies.
The total US population was estimated to consume up to 30g per day according to the 2013–2014 National Health and Nutrition Examination Survey, and on 27 February 2023, Market Share released a report indicating that the global Erythritol market was now valued at USD $380.96 million in 2021 and is expected to expand to reach USD S2102.93 million by 2027.
The researcher’s initial untargeted metabolomics studies suggested that circulating levels of multiple polyols, especially erythritol, were associated with a 3-year incident risk for major adverse cardiovascular events – MACE: death, myocardial infarction, and stroke – prompting further investigation.
“We examined postprandial erythritol plasma levels in healthy participants following consumption of an erythritol-sweetened drink, 30g, an erythritol exposure comparable to a single can of commercially available artificially sweetened beverage, a pint of keto ice cream or other foods or beverages containing erythritol.,” Dr Hazen explained.
“Among known compounds in plasma that were associated with MACE, we identified multiple polyols, including several that are commonly used as artificial sweeteners in food… yet erythritol was among the very top MACE-associated candidate molecules identified.”
Specifically, for every 1 μM increase in erythritol levels, there was a 21% and 16% increase in the adjusted HR for MACE in the US and European validation cohorts, respectively.
While plasma levels of erythritol were low at baseline (3.27–4.14 µM), they remained 1,000-fold higher for hours after ingestion and remained substantially elevated for over two days in all participants.
“We also examined the impact of erythritol on platelet function in humans at levels observed following ingestion of an artificially sweetened drink, and on in vivo thrombosis potential in animal models of arterial injury,” Dr Hazen said.
“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.
“Across the physiologically relevant concentration range observed in fasting plasma samples, erythritol dose-dependently enhanced platelet aggregation.
“In contrast, no effect on platelet aggregation responses was observed with either glucose, the most common polyol, or 1,5-anhydroglucitol (AHG), a well-established polyol surrogate of glycaemic control.”
Dr Hazen explained that measuring artificial sweeteners is already challenging, as like all polyols, the separation of erythritol from its structural isomer is difficult, hindering its analysis and quantification, but research is further hampered by minimal labelling requirements that seldom list individual compounds.
“‘Artificial sweeteners’ are typically reported in aggregate due to nondisclosure policies on food labels. This limits the specification of individual sweeteners on labels and the ability to monitor adverse long-term outcomes with individual sweeteners in clinical studies,” he said.
Further, this has led to difficulties in linking the volume of dietary artificial sweetener use with circulating levels.
“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,” Dr. Hazen said.
“Many observational epidemiological studies report that artificial sweetener use is associated with various adverse health outcomes including CVD mortality, while others do not.
“Public policy decisions need to be evidence-based and better informed… and the present results highlight the need to establish reporting requirements, safety profiles and margins of daily intake amounts given that broad consumption continues to increase.”
*Ed note: it would be interesting to examine the link between erythritol and the ‘unexplained’ MACE events currently associated in the media with COVID vaccines…