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TYPE Opinion
PUBLISHED 23 May 2023
DOI 10.3389/fnut.2023.1195521
OPEN ACCESS
EDITED BY
Nitya Sharma,
Indian Institute of Technology Delhi, India
REVIEWED BY
Marta Laranjo,
University of Evora, Portugal
*CORRESPONDENCE
Thorsten Cramer
tcramer@ukaachen.de
Barbara Kofler
B.Kofler@salk.at
RECEIVED 28 March 2023
ACCEPTED 09 May 2023
PUBLISHED 23 May 2023
CITATION
Cramer T, Gonder U and Kofler B (2023) Plasma
erythritol and cardiovascular risk: is there
evidence for an association with dietary intake?
Front. Nutr. 10:1195521.
doi: 10.3389/fnut.2023.1195521
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©2023 Cramer, Gonder and Kofler. This is an
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does not comply with these terms.
Plasma erythritol and
cardiovascular risk: is there
evidence for an association with
dietary intake?
Thorsten Cramer1*, Ulrike Gonder2and Barbara Kofler3*
1Department of General, Visceral and Transplantation Surgery, RWTH University Hospital, Aachen,
Germany, 2Nutritionist, Freelance Science Writer, Hünstetten, Germany, 3Research Program for
Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the
Paracelsus Medical University, Salzburg, Austria
KEYWORDS
erythritol, food supplement, cardiovascular risk, epidemiology, platelet function, pentose
phoshate pathway
Introduction
The sugar alcohol erythritol is naturally occurring in some fruits such as grapes, melons,
pears and fermented products like soy sauce, red wine and cheese (1). In addition, erythritol
is an endogenously occurring polyol (2). A study published in early 2023 in Nature Medicine
entitled “The artificial sweetener erythritol and cardiovascular event risk” (3) has caused
quite some controversy and uncertainty in the nutrition field inter alia clinicians and
dieticians as well as the general public. The data presented in this paper seem to be
interpreted in a way that consumption of erythritol leads to a significantly increased risk
of suffering “cardiovascular events” [death or non-fatal heart attack or non-fatal stroke,
summarized as “major adverse cardiovascular events” (MACE)].
Here, we first provide a summary of the results of the study by Witkowski and Nemet
et al. (3) and a critical evaluation of whether or not there are enough research data available
to conclude with confidence, whether or not dietary erythritol intake is associated with
enhanced cardiovascular risk or death. In addition, we briefly discuss endogenous erythritol
synthesis and selected studies reporting the effect of erythritol intake on other diseases.
Plasma erythritol levels and cardiovascular events in
patient cohorts
First, the authors used blood samples from a large cohort study (>1,100 subjects
with high prevalence of cardiovascular disease or risk factors) to perform an “untargeted
metabolomics” analysis using a state of the art, mass spectrometry-based analysis to measure
(=identify and quantify) a very large number of features in the blood of the subjects. As
such, several features (peak or signal that represents a chemical compound) from the group
of polyols (organic compounds containing several hydroxy groups (-OH), also known as
polyalcohols) were detected. In view of the fact that many sugar substitutes fall into the
group of polyols (e.g., sorbitol, xylitol, and erythritol), the authors focused their further
investigation on erythritol. Comparison of the measured levels of erythritol with the clinical
courses from the cohort patients showed that subjects who experienced MACE within 3 years
of follow-up had statistically significantly higher erythritol concentrations in their blood [see
Figure 1 in (3)].
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Cramer et al. 10.3389/fnut.2023.1195521
In the next step of their investigation, the authors established
a “targeted metabolomics” analysis in order to achieve a more
precise quantification of erythritol. This was necessary because
the above mentioned “untargeted metabolomics” analysis did not
allow an absolutely reliable differentiation between erythritol and
structurally related polyols. The improved methodology was used
to analyse blood samples from two further cohort studies from
the US and Europe (>2,200 and >800 subjects), again with high
prevalence of cardiovascular disease and risk factors, respectively.
Here, a similar picture emerged, i.e., subjects at increased risk
of MACE had statistically significantly higher blood erythritol
concentrations [see Figures 1 and 2 in (3)].
It is interesting to note that the concentration of erythritol in
the plasma of the subjects increased with age in all three cohorts.
The subjects with the highest erythritol levels (top quartile) were on
average 10–14 years older and had a higher prevalence of diabetes
than the subjects with the lowest values [lowest quartile, see Tables
S1–3 in (3)]. Still, after stratification of the results for confounding
factors such as age, body mass index and other risk factors, higher
erythritol concentration remained as an independent risk factor
in all cohorts when men and women were analyzed together.
However, when sexes were analyzed separately, no significant
association was observed in two of the three cohorts in women
[Tables S7 and S8 in (3)].
Eect of erythritol on platelet function
in vivo and in vitro
Based on the epidemiological findings, the authors
hypothesized that erythritol may modify the function of blood
platelets. The background to this hypothesis is the well-established
causal role of increased aggregation of platelets for the formation of
blood clots (thrombi) in blood vessels supplying the heart and the
brain, respectively, in the pathophysiology of myocardial infarction
and stroke. The authors used two different preparations of platelets
(platelet-rich plasma and washed human platelets) from healthy
volunteers for in vitro analyses. Erythritol significantly increased
the aggregation of human platelets in a dose-dependent manner
[see Figure 3a in (3)]. Furthermore, erythritol increased thrombus
formation in a model examining human blood under conditions
of physiological shear forces. Finally, these results were further
verified in a mouse model. Again, significant stimulatory effects
of erythritol on blood clot formation were found [see Figure 4b
in (3)].
Pharmacokinetics of exogenous
erythritol in human plasma
Lastly, the authors conducted a pharmacokinetic study with
8 healthy volunteers. In this study, volunteers had to drink
300 ml of a beverage sweetened with 30 g of erythritol within
2 min following an overnight fast. Subsequently, blood samples
were taken at specific time points and the concentration of
erythritol was determined. Within the first 30 min, there was
an up to 1,000-fold increase in erythritol concentration (basal
values: 3.84 (3.27–4.14) µM) vs. 5.85 (4.30–7.68) mM [median
(25th and 75th percentiles) at 30 min]. Remarkably, significantly
elevated erythritol concentrations were detectable in the blood of
these volunteers up to 48 h after consumption of the sweetened
beverage (3).
Discussion
Cohort studies are an excellent tool for generating hypotheses.
However, causal relationships cannot be proven by cohort studies
(4). The authors were totally aware of this limitation and they
also mention it in the discussion (“... these studies can only show
association and not causation”). Therefore, this study cannot clarify
whether the consumption of erythritol leads to an increased risk
of heart attack and stroke, and because no erythritol consumption
data were available no definitive recommendation to reduce the
consumption of erythritol can be derived from this study.
The subjects from the cohort studies had shown increased
cardiovascular risk [see supplementary tables in (3)]. Therefore, the
results of the article by Witkowski and Nemet et al. do not allow
an assessment of the effects of erythritol on the development of
heart attacks or strokes for healthy people who consume erythritol
occasionally, or even regularly, e.g. as part of a carbohydrate-
reduced diet. The authors of the study are also aware of these
correlations, as they emphasize several times that their results only
apply to people with increased cardiovascular risk.
Erythritol found in human blood can have two origins: Either
it is ingested with food (=exogenous) or it originates from
the metabolism of the subject (=endogenous). Erythritol is
constitutively synthesized in humans from glucose via the so-
called pentose-phosphate pathway, a side arm of glycolysis (2).
As discussed in depth in a recent review by Mazi et al., elevated
erythritol levels might be an indicator of pentose phosphate
pathway dysregulation resulting from glucose and fructose rich
diets (5). Interestingly, endogenous erythritol synthesis is also
elevated in response to oxidative stress (6). It is known that the
pentose-phosphate pathway is more active in subjects with pre-
existing cardiovascular disease (1,7). This could therefore explain
the elevated erythritol concentrations measured in the cohorts,
without consumption via food being a factor. This is also supported
by the fact that blood samples were obtained at a period of time
when erythritol consumption was much rarer than, say, today and
was completely absent in the first cohort (2007–2009). Two other
studies including samples from 1987 to 1989 were conducted well
before erythritol was available as a sweetener, reporting elevated
levels of it with incident diabetes and coronary artery disease (8,9).
A limitation of the study is the fact it was not possible to
determine whether the erythritol levels in plasma were influenced
by exogenous consumption, since no information on the diet or
composition of the food in the days prior to blood samples being
drawn, was collected from the subjects. This is a noteworthy caveat.
In addition, it should be noted that the older individuals with higher
erythritol levels also had greater pre-existing risk factors including
a higher prevalence of diabetes (3). It is also unknown whether
endogenous erythritol production generally increases with age.
We consider the “Erythritol intervention study” conducted by
the authors to be another weakness of the article. As described
in detail above, the “intervention” consists of the consumption of
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Cramer et al. 10.3389/fnut.2023.1195521
a 300 ml drink sweetened with 30 g of erythritol within 2 min on
an empty stomach. This is a typical “study situation” and rather
rarely corresponds to a representative breakfast meal in real life.
Erythritol-containing beverages and foods are typically consumed
throughout the day, and not within a very short timeframe.
According to the commission regulation [(EU) 2015/1832 of
12 October 2015 amending Annex II to Regulation (EC) No
1333/2008] erythritol is allowed as a flavor enhancer in energy-
reduced or with no added sugars flavored drinks at a maximum
level of 1.6 %. Thus, 300 ml of a drink can contain a maximum
of 4.8 g of erythritol. Moreover, erythritol is very often present
within a food matrix that has a delaying effect on postprandial
absorption. It is therefore questionable whether the reported
plasma concentrations also occur under “real life” conditions.
Furthermore, it is completely unclear to what extent different
diets inter alia a low-carb or ketogenic diet affect the postprandial
absorption of erythritol. The intestinal microbiome is critically
involved in the digestion and absorption of various substances, and
carbohydrate-reduced diets may critically alter the composition
of the intestinal microbiome. In contrast to other sugar alcohols
erythritol is not fermented by the gut microbiome (10).
A long-term rat study with a daily erythritol dose up to 5.2
g/kg for 2 years, which is even 100-fold more than the amount
used in the mouse thrombosis model (25 mg/kg), did not affect
kidney function, cancer incidence and survival of the animals
(11). Notwithstanding, long-term clinical studies with erythritol in
humans are lacking, a pilot study tested a daily intake of 36 g/day for
4 weeks in 24 type 2 diabetics, which led to reduced arterial stiffness
and improved endothelial function (12). As the dose provided by
the long term study is 100-fold higher than the dose used in the in
vivo study of Witkowski and Nemet et al. (3) any adverse effects
of erythritol on platelet function might be outweighed by potential
beneficial effects (5), or at the very least may not influence longevity.
In summary, the authors must be credited for not overstating
the results of their study, but explicitly pointing out in the
discussion [especially in the last paragraph, page 7 in (3)] that
their results suggest that clinical trials are needed to investigate
the relevance of erythritol (and other sugar substitutes) for the
development of cardiovascular disease using sufficient duration and
relevant clinical end points. Such a differentiated and transparent
presentation is remarkable and (unfortunately) rather not the rule
in nutritional studies.
As so often is the case with nutritional studies, the results
do not permit the derivation of recommendations. As explained
above, no causal relationship between erythritol consumption
and cardiovascular risk can be derived from the epidemiological
study results (3,8,9). Limiting the consumption of erythritol
remains an individual decision. We are aware that this is
an unsatisfactory statement, but without results from well-
designed and transparently analyzed clinical trials, a definitive
recommendation is, for the time being, not possible.
Author contributions
TC and BK contributed to the conception and design of
the opinion-study and drafted the manuscript first. UG provided
additional input and edited the manuscript. All authors contributed
to the article and approved the submitted version.
Acknowledgments
We thank William Smiles for English Editing.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
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organizations, or those of the publisher, the editors and the
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endorsed by the publisher.
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