February 27, 2023

expert reaction to study looking at an artificial sweetener (erythritol) and cardiovascular disease events

A study published in Nature Medicine looks at the artificial sweetener erythritol and cardiovascular event risk.

Prof Nita Forouhi, MRC Epidemiology Unit, University of Cambridge, said:

Comment updated 03/03/2023:

“The current research was based on a number of lines of investigation including observational and interventional research and mechanistic studies to understand the links between the artificial sweetener erythritol and cardiovascular disease.  As such it extends previous research on the potential health harms of artificial sweeteners, but generalisability of the findings is limited as the current research was in patients undergoing cardiac risk assessment not in healthy or general populations.

“The artificial sweetener erythritol was related with increased risk of new-onset major adverse cardiovascular events in three studies of stable patients undergoing diagnostic cardiac evaluation, one as a discovery cohort and two studies for validation of results from the first study.  Though the authors accounted for several risk factors for cardiovascular disease, a number of important factors were not accounted for that may significantly impact the observed associations.  These include participants’ ethnicity, socio-economic status, alcohol consumption and their diet as each of these may be related both to polyols (erythritol) consumption and to cardiovascular disease risk.  Other factors that may influence the results include the duration of known diseases such as diabetes or high blood pressure, medication use including use of statins, or drugs for management of high blood pressure or diabetes, and the degree of glucose control in those with diabetes.

“The interventional study that the researchers conducted in 8 participants showed elevation of erythritol levels after ingestion via a drink but the interpretation of the observational studies is challenging because it is unclear as to what proportions of the blood levels of erythritol are from dietary consumption versus metabolic processes that lead to its production within the body.  The distribution of levels of erythritol in the three presented studies is not clear so it is hard to see if there is a linear dose response or a threshold effect.

“The evidence is not yet definitive but highlights the importance of investment into further research.  Future research such as with long-term observational studies and appropriately designed clinical trials is still needed to establish the evidence and to determine safe levels in an environment of increasing use of artificial sweeteners.  Individual artificial sweeteners are not currently reported upon which makes their tracking difficult as well as limit the ability to readily research their health impacts.”

Prof Gunter Kuhnle, Professor of Nutrition and Food Science, University of Reading, said:

“There is an ongoing discussion of the safety of sweeteners – partly because some studies show an increased risk for chronic diseases among those who consume sweeteners, especially in soft drinks.

“It is therefore important to investigate the physiological effect of sweeteners, and this has been done in this study.  Unfortunately, the authors decided to use an amount of sweetener that is – at least in the UK and Europe – unrealistic.  The sweetener concentration they used was 10-fold higher than the permitted amount in drinks and the single dose they use was more than most of us would eat during an entire day.

“The authors also find other physiological effects of erythritol but mainly at plasma concentrations that are higher than those found in the study cohort and presumably also the general public.

“These results suggest a potentially adverse effect of erythritol when consumed a amounts above what is generally consumed in Britain or the EU – and this is one of the reason why regulators set limits for the use of food additives in sweeteners: to protect the public and ensure intake is in a safe range.

“In contrast to these data in this new study, observational studies can provide much more reliable data about links between sweetener intake and health as they reflect normal diet.  In this context, those studies measure actual intake which provides much better information on actual intake.  Unfortunately, even those studies are affected by confounding and an association between high sweetener intake and ill health might not establish a casual relationship.

“Unfortunately, the authors do not provide any information about the erythritol concentration found in the study populations and this makes an interpretation difficult.  The study’s findings are surprising as only the group with the highest plasma erythritol concentration has a higher risk of disease – but not the others.  This group also has the oldest participants, and when the authors adjust for this, the observed association with risk becomes much smaller.

“The interesting question here is the origin of plasma erythritol, as this could potentially explain some of the results: erythritol is not only used in foods but also other products such as tooth paste and drugs.  Especially the latter might affect the observed results as higher plasma concentrations could indicate that participants receive different medical treatments.

“The press release is very cautious in making a bold claim, and I agree that the information is interesting and useful, but definitely not suitable to cause anyone to worry.

“(The paper claims that erythritol has ‘generally regarded as safe’ [GRAS] status in Europe and this is incorrect.  EFSA does not have a GRAS system.)”

Prof Oliver Jones, Professor of Chemistry, RMIT University, said:

“This is a thought-provoking study based on good science.  There were a high number of study participants and the data has been well analysed.

“The authors not only found a potentially important association between levels of the artificial sweetener erythritol in the blood and health impacts, but they also took the trouble to show a viable way by which the effect they found could occur.  Although this study can’t itself show whether or not this is the case, the authors suggest that higher erythritol levels may increase the risk of blood clots forming and this in turn may increase the risk of disease.

“We should be mindful that correlation is not causation.  As the authors themselves note, they found an association between erythritol and clotting risk, not definitive proof such a link exists.

“Because the people in the study already had a lot of cardiovascular risk factors it can’t be shown that it wasn’t one of these other factors that caused the increased clotting risk rather than the erythritol.  While some effects were seen in a test with healthy volunteers, this study only had 8 people in it and only lasted a few days.  This is not enough to draw firm conclusions from, and the authors don’t try to do so.

“While I think the finding certainly warrants further investigation don’t throw out your sweeteners just yet.  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.”

Prof Tom Sanders, Professor emeritus of Nutrition and Dietetics, King’s College London, said:

“This exploratory study measured levels of numerous metabolites by mass spectroscopy in the blood of high-risk patients undergoing diagnostic evaluation for cardiovascular disease (CVD) in the USA.  About three quarters of the participants had coronary disease, high blood pressure and about a fifth had diabetes.  They then followed up these individuals over the next three years.  They found twice the risk of CVD death or events in those patients in the top quartile for the blood levels of sugar alcohols (often called polyols).  The most marked difference was with erythritol, which is used as a bulk sweetener used to replace sugar particularly in products targeted at people with type 2 diabetes.  The study replicated this finding in validation studies in the USA and Europe (Denmark).  The increased risk of CVD remained after statistical adjustment for known risk factors.  However, the adjustment did not include kidney function.  This is important because impaired kidney function results in high blood levels of sugar alcohols.  The data in Figure 2 of the paper does indicate that the risk of CVD was much greater in patients with a low glomerular filtration rate (impaired kidney function).

“To investigate the potential mechanisms by which erythritol might increase risk, the authors reported that adding erythritol to platelet rich blood plasma enhanced the aggregation of platelets in response to ADP (adenosine diphosphate).  However, there are limitations to the interpretation of these measurements.  Historically, measurements of platelet function in vitro (in a test tube) have mainly been used to demonstrate the effects of drugs that inhibit function rather than enhance it.  This study did not measure platelet function in blood from subjects following the consumption of erythritol.  Instead, the authors extrapolated effects from their in vitro measurements to predict effects based on blood levels of erythritol following the consumption of the sweetener in a different group of healthy subjects.  The findings of this study would be more convincing had the measurements of platelet function been made on platelets from subjects following the consumption of erythritol vs placebo, or better still by measuring the number of activated circulating platelets by flow cytometry.  It is also worth noting that there is only limited evidence that measurement of platelet aggregation on individuals can predict risk of CVD.  For example, the Framingham study found that increased sensitivity to ADP was associated with 16% increase in risk of heart attack or stroke.

“The presence of high levels erythritol in blood is almost certain to have been derived from the use of artificial sweeteners because the levels present in food are generally at a low concentration (0.7 – 1.3 /kg) so the amount from naturally sources is unlikely to exceed 1 g/day.  Whereas as the amount provided by it as an artificial sweetener can be as high as 30 g/day.  Erythritol unlike most other sugar alcohols is not fermented in the gut and is excreted in the urine unchanged.  Long-term toxicological studies on erythritol in animals found nothing remarkable.  The mechanism by which erythritol might affect platelet function is unclear especially as it is a relatively unreactive molecule.

“The key findings of this study are that high blood levels of erythritol are strongly associated with CVD outcomes in high risk patients which has been replicated in separate validation studies.  Diabetes UK currently advises diabetes patients not to use polyols.”

Dr Duane Mellor, Registered Dietitian and Senior Lecturer, Aston Medical School, Aston University, said:

“This is an interesting study looking at how a sweetener, a sugar alcohol or polyol, erythritol, might be associated with cardiovascular disease risk along with some of the mechanisms linked to clotting of blood – which is associated with heart disease.

“The authors look at data of populations and compare plasma (similar to blood) levels of erythritol and found those with the highest levels of erythritol had the greatest chance of having a major adverse cardiovascular event (MACE) – sometimes this combination of heart attacks and strokes is used where there is not a clear association between the risk factor, in this case erythritol, and heart attacks or strokes separately.  This could mean that the associated risk of high plasma erythritol is small and not significant for the individual types of heart disease e.g. heart attacks or stroke.

“It is also important to note this is the risk of plasma erythritol and not dietary erythritol.  This is important as there is a biochemical pathway in mammals including humans which means we can make this sugar alcohol from sugar.  This pathway, known as the pentose phosphate pathway, is typically used more when there are high levels of glucose (sugar in the body) – this happens in individuals where there is an excess of energy intake (and probably low levels of physical activity) as well as during times of oxidative stress (also associated with excess energy intake and low levels of physical activity).  So, the observation that higher levels of erythritol may not be associated with dietary intakes but instead with overall lifestyle and other risk factors is entirely plausible.  This is something the authors briefly mention, as one of the populations studied had their data collected when dietary intakes of sweeteners and processed foods in general were lower.

“In another experiment reported in this paper, the researchers gave participants 30g of erythritol in a drink and measured how it appeared in the blood.  It is important to remember that erythritol is not changed much by our bodies and about 90% is excreted in the urine.  The researchers claim that 30g per day of erythritol is a possible intake in the US, however in the UK total polyol or sugar alcohol intake (of which erythritol is one of five or six) is much lower, rarely exceeding 10g per day.  Also polyols like erythritol do occur in nature including in foods like melon and fermented foods.  It is also work noting in the UK it is recommended not to consume more than 25g of sugar alcohols in total per day as they can have laxative effects.

“However, despite what appears to be a large amount of erythritol added to the study drink, the reported effect of erythritol on blood stickiness (how it affected platelets) and other measures linked to clotting were done with samples of blood and plasma taken from volunteers, not directly in their bodies after consuming the sweetened drink.

“So, 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.  All this study has demonstrated is that erythritol may be associated with cardiovascular disease, not specifically when it is used as a sweetener.

“This study does not change advice that we should try to reduce our sugar intake and if we need to use sweeteners use them in moderation as a way to reduce sugar and ultimately sweet tasting foods and drinks in our diet.

‘The artificial sweetener erythritol and cardiovascular event risk’ by Marco Witkowski et al. was published in Nature Medicine at 16:00 UK time on Monday 27 February 2023.

DOI: 10.1038/s41591-023-02223-9

Declared interests

Prof Nita Forouhi: “None.”

Prof Oliver Jones: “I don’t have any conflicts of interest to declare although I do work in the field of metabolomics (the study of small biological metabolites) which is one of the main techniques used in this paper.”

Prof Tom Sanders: “I used to act as a consultant on Isomaltose, which is a polyol (Zudzucker) over 12 years ago.  I have no relevant conflicts of interest over the past 3 years.”

Prof Gunter Kuhnle: “No COI.”

Dr Duane Mellor: “No conflict of interest.”