Sweeteners: erythritol, xylitol and cardiovascular risk—friend or foe?

Abstract

Hyperglycaemia harms vascular health and promotes platelet aggregation. Reducing glucose concentration is crucial, and sugar alcohols may aid this effort. Used for over 50 years in food, cosmetic, and pharmaceutical industries, erythritol and xylitol minimally affect plasma glucose and insulin levels while promoting the release of beneficial gastrointestinal hormones such as e.g. glucagon-like peptide-1. These properties make them particularly appealing for individuals with diabetes, obesity, and metabolic syndrome. Recent pilot trials suggest that xylitol and erythritol might temporarily alter platelet aggregation. Studies on critically ill patients receiving large intravenous doses and Mendelian randomisation trials do not link sugar alcohols to significant cardiovascular risks. Sugar alcohols are also endogenously produced in the body, and while their increased production under certain conditions is not fully understood, it requires further research. This review discusses the physiology and metabolism of erythritol and xylitol, and other sugar alcohols, their roles in metabolomic profiling, effects on platelet aggregation and cardiovascular risk, related genetic disorders, vascular impacts, and usage in critically ill patients.

Time of primary review: 30 days

1. Introduction

Sugar alcohols, particularly erythritol and xylitol, have been implicated in increased cardiovascular (CV) risk, although a direct causal relationship between their use and CV events is lacking. Given their widespread use in food products and pharmaceutical formulations, it is crucial to comprehensively evaluate the existing data. This review explores the physiology and metabolism of erythritol and xylitol, and other sugar alcohols, their roles in metabolomic profiling, their effects on platelet aggregation and CV risk, associated genetic disorders, vascular impacts, and their application in critically ill patients.

2. Physiology and metabolism of erythritol and xylitol

Erythritol and xylitol are naturally occurring sugar alcohols found in berries and vegetables, with broad applications in the food, pharmaceutical, and cosmetic industries.^1–3 Upon ingestion, erythritol is rapidly absorbed in the small intestine, with most excreted unchanged in the urine and a small portion metabolized to erythronate.⁴ The absorption rate is dose-dependent, as demonstrated in a recent trial where higher doses (50 g) resulted in slower absorption compared with lower doses (10 g, 25 g), suggesting a saturable process.⁴ Ingestion of erythritol results in elevated plasma erythritol concentrations, with maximum levels (Cmax) reached within 30–60 min: Cmax 1810.6 ± 124.6 μM (10 g), 3676.9 ± 251.2 μM (25 g), and 5404.3 ± 450.6 μM (50 g).⁴ Similarly, Hootman et al.⁵ reported that ingesting 50 g of erythritol raised plasma levels to ∼5500 μM within 50 min.⁵ In a recent trial ingestion of 30 g of erythritol resulted in plasma concentrations peaking at 7680 μM after 30 min.⁶ In this trial, plasma erythritol concentrations were measured up to 7 days post-ingestion, with elevated concentrations persisting for up to 2 days compared with baseline.⁶

In contrast, xylitol is only absorbed 50% and mainly metabolized in the liver, while the non-absorbed fraction enters the colon. This partial absorption explains why rapid ingestion of large amounts of xylitol can lead to osmotic diarrhoea. Following a 30 g dose of xylitol, plasma xylitol concentrations were found to peak at ca. 630 µM approximately 30 min post-ingestion return to baseline within 4–6 h.⁷ Absorption studies have so far been conducted exclusively in healthy individuals. However, in people with obesity or diabetes, altered digestive, metabolic, or renal functions could influence how these sugar alcohols are absorbed, metabolized, and excreted. In the colon, xylitol is fermented by gut microbiota and studies with human faecal cultures suggest xylitol might act as a prebiotic, increasing the formation of short-chain fatty acids such as butyrate.^8,9 The absorbed part of xylitol is further metabolized mainly in the liver within the non-oxidative branch of the pentose monophosphate shunt to produce first D-xylulose and then D-xylulose 5-phosphate (Xyl-5-P), the latter being rapidly converted to glycolytic intermediates.¹⁰ While consumption of erythritol has no impact on plasma glucose and insulin levels, xylitol leads to a small increase.¹¹

A long-term feeding trial on xylitol was carried out in 1972–1974 in Turku, Finland. In this trial, 125 healthy subjects lived on strict diets over 2 years and received sucrose, fructose, or xylitol ad libitum as their only sweetener to study the impact on oral health. Subjects in the xylitol group (n = 52) consumed an average of 67 g of xylitol per day, but the highest daily doses of xylitol were 200–400 g per day. A total of 35 subjects in the xylitol group were considered to have consumed exceptionally high quantities of xylitol (100–149 g/d). Medical research teams continuously monitored all participants, and no adverse events were registered besides some dose-dependent gastrointestinal discomfort.¹²

More recent studies have repeatedly demonstrated that acute erythritol and xylitol consumption—despite their lack in calories—trigger gastrointestinal satiation hormones (incretins) release (namely cholecystokinin, glucagon-like peptide-1, and peptide tyrosine tyrosine), and erythritol has also been shown to lower concentrations of the hunger hormone ghrelin.^11,13–15 Downstream effects of gastrointestinal hormones (e.g. a dose-dependent delay in gastric emptying rates in response to erythritol and xylitol intake and activation of brain networks involved in regulating appetite and reward) could also be observed.^11,13,16 Moreover, a beverage (preload) sweetened with erythritol leads to a significant decrease in subsequent energy intake from an ad libitum buffet meal compared with preloads sweetened with sucralose or sucrose or plain water (placebo), which demonstrates the satiating effect of erythritol.¹⁷ However, data on the long-term effects of daily xylitol or erythritol consumption on caloric intake or body weight are not yet available Figures 1 and 2.

Figure 1.

Sugar, erythritol and xylitol and the vascular system. NADPH, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species.

Figure 2.

Different effects of sugar alcohols. ATP, adenosine triphosphate; CCK, cholecystokinin; CKD, chronic kidney disease; CVD, cardiovascular disease; GLP-1, glucagon-like peptide-1; PYY, peptide tyrosine tyrosine; SCFA, short chain fatty acids; T2DM, type 2 diabetes mellitus.

3. Genetic disorders involving components of the hexose monophosphate shunt

In hereditary metabolic disorders caused by deficiencies in transaldolase (TAL), transketolase (TKL), or sedoheptulokinase (SHK), plasma concentrations of endogenously produced erythritol and other sugar alcohols are chronically elevated:

In TAL-deficiency, patients present with hepatosplenomegaly, congenital heart defects, abnormal liver function, cholestatic jaundice, elevated liver enzymes, hepatic fibrosis or cirrhosis, haemolytic anaemia, thrombocytopenia and abnormal skin (e.g. cutis laxa).^18–20 TAL-deficiency results in the accumulation of several metabolites (e.g. sedoheptulose, mannoheptulose, sedoheptulose 7-phosphate, erythritol, arabitol, ribitol, sedoheptitol and perseitol, and erythronic acid.^18,20

In TKL-deficiency, patients present with short stature, developmental delay, congenital heart disease, and cataracts.²¹ TKL-deficiency results in elevated concentrations of several metabolites: Elevated urinary excretion of erythritol, arabitol, ribitol, and pent(ul)ose-5-phosphates, as well as elevated plasma concentrations of erythritol, arabitol, and ribitol.

Isolated deficiency in SHK is a rare, hereditary disorder characterized by high urine levels of sedoheptulose and erythritol, and low-to-normal excretion of sedoheptulose-7P.²² Two patients described with SHK-deficiency presented with neonatal cholestasis, hypoglycaemia, respectively, congenital arthrogryposis multiplex, multiple contractures, and dysmorphisms.²² Although patients with these genetic conditions exhibit chronically elevated erythritol levels, none appear to increase the risk of blood clot formation.

In pentosuria, a benign and asymptomatic inborn error of metabolism, 1–4 g per day of pentose L-xylulose is excreted in the urine and the plasma concentration of xylulose reaches 80 µM.²³

Given its structural similarity to xylitol, xylulose ought to exhibit comparable chemical actions, potentially enhancing stimulus-induced platelet aggregation in response to multiple agonists (e.g. ADP, thrombin, collagen) and promoting thrombus formation in vivo—unless the supposed ‘pharmacological’ effect of xylitol on platelet aggregation is extremely specific. The studies by Witkowski et al.⁷ were conducted at a xylitol concentration almost three times lower (30 µM) than the plasma concentration of xylulose in pentosuric subjects. Interestingly, despite the elevated xylulose levels, pentosuria is harmless and not associated with health problems.

4. Sugar alcohols in metabolomic profiling studies

Metabolites are molecules formed as by-products or end-products of metabolic processes, potentially serving as biomarkers for health and disease. Apart from the exogenous supply through natural sources (e.g. berries, mushrooms, cauliflower) and by use as a sweetener, erythritol and xylitol are also endogenously produced by the human body (=metabolites)—as are other sugar alcohols (e.g. mannitol, sorbitol, ribitol).^5,10 Approximately 5–15 g of xylitol is formed endogenously in the human body daily.²⁴ Under certain conditions, endogenous production of sugar alcohols increases. The reason why the body produces more sugar alcohols in these cases is still largely unexplored. Recent studies by Witkowski et al.⁷ suggested that higher fasting plasma concentrations of the two metabolites erythritol and xylitol are associated with increased CV risk and might predict major adverse cardiovascular events (MACE).^6,7 Unfortunately, as in many other metabolomic profiling studies, dietary intake of the two substances was not assessed and therefore the source of the two substances (endogenous vs. exogenous) remains unclear. In a trial published by Wang et al.²⁵ in 2019, serum samples were prospectively collected from >3500 patients in 1987–1989 and elevated erythritol levels were found to be associated with increased risk for coronary heart disease.²⁵ However, erythritol had only been approved by the FDA for use as a food additive in the US in 2001, and therefore, erythritol found in these blood samples must have been from endogenous synthesis.

In the recent study by Witkowski et al.,⁶ where plasma erythritol levels were associated with increased MACE risk, the majority of investigated subjects (‘US validation cohort’) were also enrolled before erythritol was used as a sugar substitute and therefore erythritol levels most likely reflect endogenous production. The EU validation cohort enrolled patients more recently (until 2018) when erythritol was used on the EU market. The authors, therefore, speculate that erythritol levels in their EU cohort originated from a combination of ingestion and endogenous production.⁶ However, at the time, erythritol was still a niche product in Europe, with limited consumption, particularly among individuals over 60 years of age. This suggests that the observed findings likely reflect primarily endogenous production. The same authors found also elevated xylitol concentrations to be associated with increased MACE risk.⁷ Xylitol has been used as a sweetener in the US and Europe since the 1960 / 1970's. However, as plasma xylitol levels rapidly return to baseline (=fasting) concentrations within hours after ingestion, the fasting plasma levels observed in their observational cohort represent endogenous production and are independent of dietary xylitol intake.⁷ Although derived from the same patient cohorts, the authors separately published findings linking circulating plasma erythritol and xylitol levels to an increased risk of MACE, based on targeted metabolomics analysis.^6,7 Metabolomic analyses usually yield an abundance of metabolites, and clusters of metabolites (in this case, sugar alcohols) are described to highlight patterns and relationships. In their initial publication, untargeted metabolomics revealed that elevated plasma concentrations of several sugar alcohols (e.g. arabitol, erythritol, xylitol, myoinositol, threitol) and other metabolites were linked to MACE, consistent with prior studies.⁶ However, the focus was primarily on erythritol and xylitol, given their dual role as metabolites and sweeteners. This raises the question of whether erythritol levels were elevated to the same extent as xylitol and other sugar alcohols (e.g. ribitol, sorbitol, mannitol) or if metabolites from other categories were similarly increased in the same patients studied by Witkowski et al.⁶

Previous studies have also found elevated circulating concentrations of erythritol precede coronary heart disease,^25,26 associated with diabetes,^27,28 obesity,⁵ and arterial stiffness,²⁹ and may therefore be a marker of impaired metabolism. The endogenous production of a variety of sugar alcohols—such as mannitol, sorbitol, lactitol, ribitol, and arabitol—appear up-regulated in other diseases, which could be shown, e.g. in tissue samples of hepato-cellular carcinoma,³⁰ and serum samples of stroke patients.³¹ In major trauma patients, a metabolomic signature for patients with a prolonged intensive care unit (ICU) stay revealed that—amongst other metabolites—increased xylitol levels seemed of predictive value.³² Also, in a large epidemiological study with over 11’000 subjects using data from the EPIC-Norfolk cohort, the metabolites erythritol, erythronate, ribitol, arabitol, xylitol, and myo-inositol were found to be associated with an increased hazard ratio for several diseases (e.g. renal disease, heart failure, peripheral artery disease, ischaemic heart disease, and stroke).³³

Interestingly, some studies report a decrease in plasma sugar alcohol levels in patients after a weight-loss program. From the POUNDS lost trial—a weight loss program in overweight and obese but normoglycemic patients who were followed over 2 years—higher levels of erythritol, its metabolite erythronate as well as other sugar alcohols, such as mannitol, sorbitol, myoinositol, arabitol and xylitol, were related to a higher atherosclerotic cardiovascular disease (ASCVD) risk.^34,35 Elevated erythritol levels were also found to be related to insulin resistance (IR). Weight loss led to a decrease in plasma erythritol concentrations, and the authors found a significant association between changes in erythritol and a reduction in fasting insulin. More pronounced decreases in erythritol in response to the weight loss intervention were also significantly related to greater reductions in ASCVD risk estimates. The 6-month decrease in erythritol was associated with long-term (2-year) improvements in atherogenic lipids.^34,35 Also, in another weight-loss program—the randomized controlled Diabetes Remission Clinical Trial (DiRECT)—participants in the intervention group were found to have reduced levels of erythronate and related metabolites (such as ribitol and erythritol).³⁶ Lastly, metabolite profiling of obese individuals before and after a 1-year weight loss program revealed that lower baseline levels of xylitol predicted a more significant decrease in body weight and erythritol levels decreased in response to weight loss.³⁷

Overall, the traditional limitation of all these observational clinical studies is that, by design, they can only show association, not causation. In addition, unmodelled confounding variables (e.g. diet) may have influenced their results (directly or indirectly) by factors not included in their models. Moreover, although factors like diet, medications, and the gut microbiome can influence metabolite levels, the metabolome is highly heritable and significantly shaped by genetic factors.^38–40 Recent genome-wide association studies have identified variants strongly associated with circulating erythritol concentrations, including variants near TKT (encoding TKL) and AKR1A1 (encoding Aldo-Keto Reductase Family 1 Member A1).^39,40 Based on these observations, Khafagy et al.³⁸ carried out bidirectional Mendelian randomisation to investigate the potential causal associations between circulating plasma erythritol and associated cardiometabolic disease.³⁸ Mendelian randomisation analyses did not find evidence for a causal association between circulating erythritol and coronary artery disease, diabetes, fasting glucose, eGFR, or chronic kidney disease, nor was any evidence found that the evaluated cardiometabolic and anthropometric traits significantly influenced erythritol concentration. Rather, Mendelian randomisation indicated erythritol may decrease BMI.³⁸

Why endogenous production of sugar alcohols is found in certain diseases remains unclear. One suggestive possible explanation would be hyperglycaemia, which is common in people who are overweight or have diabetes, as well as in people with a high intake of sugar. Chronic hyperglycaemia can trigger several additional glucose-utilizing pathways, including the polyol, hexosamine, and pentose monophosphate shunt pathways.^41,42 In mice, increased urine secretion of erythritol is found when they are fed a sucrose diet over several weeks.⁴³ An upregulation of these alternative metabolic pathways might—in theory—explain the association of increased levels of erythritol and xylitol with MACE, as hyperglycaemia and diabetes are known risk factors for MACE. However, in the studies by Witkowski et al.,⁶ analyses were adjusted for age, sex, BMI, presence of diabetes, systolic blood pressure, current smoking status, and blood lipids.⁶ The authors report that the association between higher erythritol levels and MACE risk was independent of whether the cohorts were stratified into patients with high or low blood glucose or with/without diabetes.⁶ Also, in their Mendelian randomisation trial, Khafagy et al.³⁸ could not find evidence that erythritol increases fasting glucose and type II diabetes, nor did they find evidence that cardiometabolic traits significantly influence erythritol concentration.³⁸

Recent in vitro trials on cardiomyocytes suggest that oxidative stress leads to an overproduction of sugar alcohols such as sorbitol, L-arabitol, xylitol, or dulcitol.⁴⁴ Interestingly, several sugar alcohols appear to possess antioxidant properties.⁴⁵ One may wonder whether the increased production of sugar alcohols in connection with hyperglycaemia is a kind of rescue attempt and serves to both increase utilisation of glucose and to counteract oxidative stress. With the increasing consumption of erythritol and xylitol among individuals at higher cardiometabolic risk (e.g. those with obesity and/or diabetes) in recent years, future observational studies should also consider the potential for reverse causality.

While elevated circulating plasma concentrations of erythritol, xylitol, and other sugar alcohols are associated with various diseases, the underlying cause remains unclear. Future studies should definitely take into account the participants' dietary habits (i.e. consumption of erythritol and xylitol as sweeteners but also intake from natural sources).

5. Impact of sugar alcohol consumption on gut microbiota composition and function

The potential impact of sweeteners on gut microbiota and their implications for metabolism, especially glucose tolerance, has attracted considerable attention recently. However, human intervention studies on this topic are limited. Evidence suggests that artificial non-caloric sweeteners like sucralose and saccharin may negatively impact gut microbiota composition and potentially promote metabolic diseases (e.g. impaired glycemic control), rather than preventing them.^46,47 In contrast, human intervention studies on sugar alcohols have indicated that isomalt, lactitol, maltitol, and xylitol may positively influence gut microbiota composition.^48–50In vitro and ex vivo studies using gut microbiota from healthy donors also suggest that some sugar alcohols exhibit prebiotic properties. A recent ex vivo study on the functional role of various sweeteners found significant metaproteomic alterations with xylitol, isomalt, maltitol, lactitol, sorbitol, and mannitol, while erythritol did not induce such changes.⁵¹In vitro studies have shown that isomalt is metabolized by bifidobacteria strains, leading to high butyrate concentrations.⁴⁸ Various in vitro and ex vivo studies have demonstrated that xylitol also increases butyrate and propionate production.^8,9,52 Notably, the butyrate production with xylitol is significantly higher compared with common prebiotics such as fructo-oligo-saccharides and galacto-oligo-saccharides.^8,9 Short-chain fatty acids like butyrate and propionate are beneficial in that they provide energy to the colonic epithelial cells, and play an important role in maintaining gut immunity, and in supporting gut barrier function.⁵³ A recent ex vivo study using a dynamic simulator of the colonic microbiota inoculated with pooled faecal samples from children found that xylitol dose-dependently increased the abundance of Lachnospiraceae, particularly Blautia, Anaerostipes, and Roseburia, and enhanced butyrate production, improving epithelial integrity in Caco-2 cells.⁵² The species Blautia wexlerae has been linked to potential benefits in reducing obesity and type II diabetes.^54,55

While a significant proportion of xylitol enters the colon, erythritol is mostly absorbed in the small intestine.⁴ Moreover, erythritol, which is only minimally available to the colon, appears non-fermentable, as shown in studies with fresh human faecal microbiota.⁵⁶ Overall, xylitol appears to have prebiotic effects, whereas erythritol likely has no impact on the gut microbiota. However, long-term controlled human intervention trials investigating the effects of xylitol and erythritol are still needed.

6. Effects of erythritol and xylitol on vascular function

Endothelial dysfunction and arterial stiffness are critical factors in the development of CV disease in individuals with diabetes mellitus. One important contributing factor leading to endothelial dysfunction is hyperglycaemia which promotes oxidative stress.⁵⁷In vivo, administration of erythritol prevents endothelial dysfunction in diabetic rats and in vitro tests show that erythritol—and other sugar alcohols—are potent hydroxyl radical scavengers.⁴⁵ Extensive in vitro studies on human umbilical vein endothelial cells, confirmed that erythritol exerts a number of endothelium-protective properties under hyperglycaemic conditions.⁵⁸ In a pilot trial in patients with diabetes, vascular function in response to acute (2 h after 24 g of oral erythritol) and chronic (36 g/d over 4 weeks) erythritol consumption was examined. This study found that erythritol consumption acutely improves small vessel endothelial function (fingertip peripheral arterial tonometry), and chronic treatment reduced central aortic stiffness (decreased central pulse pressure).⁵⁹ In a randomized controlled trial (RCT) on obese normoglycemic patients, no statistically significant effect of erythritol or xylitol intake on vascular function (left-brachial pulse wave velocity and arteriolar-to-venular diameter ratio) was observed.⁶⁰ The discrepancy in these two in vivo human studies may be due to differences in glycemic control: as erythritol seems to act as an antioxidant, an effect might only be seen in hyperglycaemic patients.

In the context of vascular health, it's noteworthy that xylitol appears to impact skin collagen, which may also be relevant for vascular collagen. A 3-month study in healthy and diabetic male rats showed that dietary xylitol (10%) increases hydroxyproline levels and skin thickness in healthy rats.⁶¹ In diabetic rats, acid-soluble collagen levels, initially lower than in healthy controls, rose significantly with xylitol, while collagenase-soluble levels remains unchanged. Xylitol reduces hexose content and collagen fluorescence, suggesting it influences both collagen synthesis and glycosylation.⁶¹In vitro studies revealed varying protective effects of sugar alcohols, with erythritol being most effective, followed by xylitol, against collagen denaturation by guanidine hydrochloride.⁶² The presence of OH groups in sugar alcohols likely stabilizes collagen by forming additional hydrogen bonds.⁶² Further investigation is needed on the effect of erythritol and xylitol on human vascular collagen.

In the context of vascular health, also the NADPH-generating effect of xylitol should be mentioned. Human erythrocytes contain an NADP-linked xylitol dehydrogenase capable of regenerating NADPH by oxidising xylitol to L-xylulose.⁶³ NADPH is critical in preventing damage to cellular structures caused by an oxidative challenge by serving as a substrate for the enzyme glutathione reductase. Reduced glutathione can be used to convert hydrogen peroxide to water and prevent damage to cellular structures, particularly the cell walls of red blood cells (RBCs), which have limited ability to repair themselves once they mature.⁶⁴ Therefore, xylitol can be of pharmaco-medical use to improve glucose-6-phosphate dehydrogenase deficiency anaemia, the most common inborn enzyme disorder in all populations.⁶⁵In vivo studies in rabbits have clearly shown that xylitol improves acetylphenylhydrazine-induced haemolytic anaemia.^63,66 In fact, compared with rabbits injected intraperitoneally with acetylphenylhydrazine alone, the infusion of an isotonic xylitol solution was found to maintain and restore hematological parameters, such as packed cell volume, haemoglobin concentration, reduced glutathione content, reticulocyte count and erythrocyte survival.⁶⁶Figure 3.

Figure 3.

Xylitol and erythritol: proven benefits, emerging opportunities, and potential risks. CCK, cholecystokinin; GLP-1, glucagon-like peptide-1; G6PD, glucose-6-phosphate dehydrogenase; PYY, peptide tyrosine tyrosine.

7. Platelet aggregation and CV risk

Various effects associated with high added sugar consumption, such as hypertension, inflammation, weight gain, IR, diabetes, dyslipidemia, and fatty liver disease, contribute to increased CV disease.^67,68 Hyperglycaemia and IR lead to a prothrombotic state in diabetic patients with changes in platelet numbers and activation, which leads to platelet hypersensitivity, coagulation disorders, and hypofibrinolysis.⁶⁹ Both acute and chronic hyperglycaemia contribute to this procoagulant state in diabetic and non-diabetic subjects.^70,71 An anti-aggregating treatment with aspirin is often recommended for diabetic patients in secondary prevention of atherothrombotic CV events, but also in primary prevention in the case where at least one additional major risk factor for CVD is present.⁷² However, high plasma glucose levels acutely reduce the anti-aggregating effect of aspirin.⁷³ Therefore, patients with diabetes and healthy subjects are advised to limit sugar intake. Sugar replacement with various alternatives can—in part—help to meet this goal. However, questions arise about whether these substances are a better choice concerning CV risk. While an increase in circulating erythritol and xylitol production was found to be associated with an increased risk of a major cardiovascular event (MACE), Witkowski et al.⁷ postulated that there might also be direct effects of these substances that lead to increased CV disease.^6,7,74 In their publications, they presented data from various tests: in vitro tests on human thrombocytes exposed to erythritol or xylitol, in vivo clot formation in a murine model, and ex vivo data from thrombocyte stimulation tests of healthy human subjects consuming xylitol or erythritol. When human platelet-rich plasma from healthy volunteers are exposed to erythritol, platelets showed a dose-dependent increase in aggregation in response to the stimulators ADP and TRAP6.⁶ Erythritol exposure increases intracellular calcium levels and enhances platelet activation markers such as P-selectin expression and GP IIb/IIIa activation. These findings suggest erythritol directly influences platelet activity, potentially contributing to clot formation.⁶ Analogue studies were carried out with xylitol with similar results.⁷ Their findings revealed that exposure to the two substances enhanced thrombin-induced calcium release in platelets. Additionally, platelet activation markers, such as P-selectin expression and glycoprotein activity, were elevated, indicating increased platelet responsiveness.^6,7,74 However, in vitro thrombocyte stimulation tests are of limited significance and cannot be easily transferred to the in vivo conditions in the human body. For instance, in vitro, acute hyperglycaemia induces platelet hyperreactivity to agonist stimulation by increasing osmolarity, subsequently affecting intracellular signalling in platelets.⁷⁵ It is possible that high concentrations of xylitol or erythritol may induce platelet hyperreactivity by increasing osmolarity, although the molecule per se has no specific thrombogenic effect.

Using a FeCl₃-induced carotid artery injury model in mice, Witkowski et al.⁶ observed that elevated erythritol levels significantly increase the speed of clot formation and reduce the time until blood flow ceased.⁶ However, in this murine model, erythritol was administered intravenously, which might have led to an osmotic stimulation of thrombocyte aggregation and impacted clot formation. In the case of xylitol, the authors had to inject xylitol intraperitoneally as it was not absorbed enough in the mice's intestines when given orally.⁷ Detailed long-term feeding trials (up to 2 years) in rats and mice with both erythritol and xylitol (using diets containing up to 20% of these substances) did not report abnormalities in CV events and no reduction in lifespan.^76–78

In separate parallel pilot trials authored by Witkowski et al.,⁷ 10 healthy human subjects were given either 30 g of xylitol, or 30 g erythritol, or 30 g glucose per os, and the blood platelet response to ex vivo stimulation with TRAP6 and ADP was examined at baseline and once after 30 min.^7,74 In these trials, increased platelet responsiveness was observed following xylitol and erythritol ingestion, while in contrast, glucose had no effect. Previous studies demonstrate that hyperglycaemia induces platelet activation in healthy and diabetic individuals. However, higher blood glucose levels or chronically elevated glucose levels are probably needed.^70,71 With 10 subjects in each group, the studies on humans were small; there was no placebo arm, and only a single time point after ingestion was investigated (after 30 min). Also, the parallel design does not allow to directly comparing the effects of the three sweeteners in the same subject. It should be noted that environmental influences affect short-term platelet responsiveness, e.g. acute physical activity can increase platelet aggregation and the tendency to aggregate can be reduced or increased post-prandially in response to various foods.^79–83 While these findings by Witkowski et al.⁷⁴ warrant further research, at this point it is not clear whether the described effect can be replicated in larger placebo-controlled randomized studies, whether the effect is also found in vivo (rather than ex vivo), whether it is only a short-term phenomenon (as with other post-prandial observations), whether the observations are of clinical significance, and which underlying mechanisms might explain the findings. According to the NCT registry, two independent research groups are currently investigating the effects of erythritol and/or xylitol on human platelet responsiveness in vivo (NCT 05967741 and NCT 04966299).

Whether other sugar alcohols have any effects on platelet responsiveness remains to be determined. Mannitol, which can be used in the treatment of raised intracranial pressure, has been studied in detail and does not seem to affect platelet function: patients undergoing elective craniotomy due to a brain tumour with elevated intracranial pressure received 1 g/kg mannitol within 30 min intravenously, and no clinically relevant changes in platelet function were found after 60 min.⁸⁴ Similarly, mannitol is a common component in almost all currently licenced storage additives for packed RBC products, which are routinely transfused to coagulopathic patients, including massively transfused critically ill patients or chronically transfused patients with hemoglobinopathies such as sickle cell disease, in which hypercoagulability is a common comorbidity.⁸⁵ Furthermore, research has shown that an extract of alditols and monosaccharides (AME) derived from sorghum vinegar, a traditional Chinese medicine, can effectively inhibit multiple stages in the process of platelet aggregation.⁸⁶ AME demonstrates strong inhibition of cyclooxygenase-1 (COX1) and thromboxane A2 synthase (TXS), as well as reduction of thromboxane A2 (TXA2) production. Computational docking studies suggest that alditols like erythritol and xylitol, but also arabitol and sorbitol can directly bind to the active site of COX, indicating a potential anti-thrombotic effect of these substances.⁸⁶

8. Diabetes and obesity

In both diabetic and non-diabetic animal models the favourable effects of oral xylitol and erythritol supplementation on glucose and lipid homeostasis have repeatedly been observed.^87–89 Investigating the mechanisms behind the antihyperglycemic effects, several mechanisms could be found: a dose-dependent inhibition of alpha-amylase and alpha-glucosidase, decreased small intestinal glucose absorption, increased muscle glucose uptake, and significantly delayed gastric emptying.^90,91 In humans with or without obesity, both acute erythritol and xylitol ingestion also delays gastric emptying.¹¹ However, in patients with obesity, daily intake of 36 g erythritol or 24 g xylitol over 5–7 weeks had no impact on small intestinal glucose absorption assessed by means of 3-Ortho-methyl-glucose.⁹² Whether the inhibition of alpha-amylase and alpha-glucosidase and/or increased muscle glucose uptake also play a role in the human body, has not been examined so far.

9. Beyond sweetness: use of xylitol instead of glucose in critically ill patients

A key component of the increased CVD risk in diabetic and non-diabetic patients is selective IR.^93–97 The selectivity of IR is based on the observation that not all insulin signalling pathways are affected by IR. As a result, the pathways that still respond normally to insulin may become overstimulated due to the compensatory increase in insulin levels.⁹⁸ One of the first and well-established evidence of such differential loss of responsiveness originated from studies conducted in endothelial cells on the pro-atherogenic and anti-atherogenic insulin signalling arms, Ras/Raf-MAPK-ERK and IRS-PI3K-Akt, respectively.^99–101 The differential decrease in insulin responsiveness by the two main branches of insulin signalling causes an imbalance in the effects of insulin on the endothelium, leading to the development of a pro-atherogenic profile.

IR can result directly from hyperinsulinemia due to the downregulation of the plasma membrane insulin receptor following chronic exposure to elevated circulating concentrations of the hormone.^102,103 This tends to happen after significant and prolonged exposure to high insulin levels, especially when induced through medication or continuous parenteral glucose infusion, which is the most powerful insulin secretagogue. Hyperglycaemia is associated with adverse clinical outcomes in critically ill patients regardless of diabetes status.^104–106 Proposed causes of stress-induced hyperglycaemia include excessive counterregulatory hormones (e.g. corticosteroids, glucagon, growth hormone, catecholamines) and release of the cytokines tumour necrosis factor (TNF)-alpha and interleukin (IL)-1. These factors can promote a transient state of IR, leading to reduced insulin action to suppress gluconeogenesis and reduced insulin-mediated skeletal muscle glucose uptake.¹⁰⁵ Factors contributing to hyperglycaemia in hospitalized patients include medications (e.g. steroids, catecholamines), parenteral nutrition and intravenous drugs diluted in dextrose. To mitigate this hyperglycaemic condition in critically ill patients, xylitol can be used as a sugar substitute, either as a stand-alone ingredient or as a component of infusional products for clinical parenteral nutrition.¹⁰⁷ The low glycemic and low insulinemic indices of xylitol are highly desirable effects in critically ill patients,¹¹ where hyperglycaemia and/or insulin-resistant states are associated with increased mortality. In addition, limiting renal exposure to glucose is particularly important in diabetic patients. Glucose in the glomerular filtrate is reabsorbed in the proximal tubule by the combined action of the sodium-glucose cotransporters (SGLT) 2 and 1. The synergy of both SGLTs is responsible for a maximum reabsorption capacity of ∼2.5 mol (450 g) of filtered glucose per day.¹⁰⁸ Since glucose reabsorption is coupled to sodium reabsorption via an energy-driven process, it explains why the kidney is a primary target of diabetes¹⁰⁹ and why total body sodium concentration is affected, driving hypertension in most diabetics.¹¹⁰

The BfArM in Germany (Bundesinstitut für Arzneimittel und Medizinprodukte, the largest drug regulatory authority in Europe) and the Pmda in Japan (Pharmaceuticals and Medical Devices Agency) have approved a maximum intravenous dose of xylitol of 3 g/kg/day and 100 g/day, respectively. In a parallel trial, Schneider et al.¹¹¹ treated 55 ICU patients with a complete parenteral nutrition solution containing 50 g of xylitol and 100 g glucose per 1000 mL.¹¹¹ In this group, a maximum of 120 g xylitol was given per day. The control group comprised 56 patients who received complete parenteral nutrition without xylitol, containing 150 g glucose/1000 mL. In the xylitol-group, serum levels of xylitol were measured and reached 3.4 mg/dL (range 0.00–7.84 mg/dL). Twenty per cent of the patients receiving xylitol had stable glucose levels and did not need insulin compared with only 7.1% of the controls. Patients receiving xylitol required 32.6% less insulin than the control group, despite receiving a comparable amount of energy (xylitol: 810.1 kcal/d; controls: 789.8 kcal/d). In this trial, no adverse effects attributable to parenteral nutrition containing xylitol were observed. Furthermore, there was no difference with regard to adverse events between the two patient groups.

In the literature, the only harmful side effect reported after intravenous xylitol administration, though extremely rare, is severe secondary oxalosis. This has been observed following the infusion of very high doses of xylitol above 300 g/day. A recent case in Japan described a patient who received a maximum dose of 500 g/day, with a cumulative total of 2925 g over eight days.¹¹² Unfortunately, in this and a few other case reports of severe secondary oxalosis, no details were provided regarding the potential presence of a loss-of-function mutation in genes involved in primary hyperoxaluria in these patients; a congenital autosomal recessive disorder associated with liver enzyme deficiency leading to massive cortical nephrocalcinosis and subsequent renal failure.¹¹³

Xylitol is currently also in clinical development as an osmo-metabolic agent for treating kidney failure patients on peritoneal dialysis (PD), a home-based renal replacement therapy alternative to haemodialysis.^114–116 In addition, a xylitol-based peritoneal ultrafiltration solution is in Phase II/III clinical development for treating congestive heart failure patients refractory to diuretic therapy.¹¹⁷ The basic concept is to replace most of the glucose used as an osmotic agent in PD therapy with two more biocompatible osmotic agents, xylitol and carnitine, since glucose has long-term pro-fibrotic effects on the peritoneal membrane, which can ultimately lead to ultrafiltration failure of the peritoneal membrane, forcing the patient to abandon this dialysis modality.^118,119 In addition to this undesirable local effect, glucose absorption from the dialysate further aggravates the already compromised metabolic state, as diabetes is a common co-morbidity in patients with renal failure.⁹⁸

Therefore, glucose's local and systemic effects exacerbate the CV risk in these patients. Replacing glucose in PD therapy with xylitol would limit the hyperinsulinemic state and, consequently, the extent of a pro-atherogenic selective IR condition.^93–98 Moreover, overexposing the liver to xylitol may also lead to an insulin-independent improvement of glycemic control since a crucial intermediate in the metabolism of liver xylitol is D-xylulose-5-phosphate (Xyl-5-P).¹⁰ This compound influences the concentration of fructose 2,6-bisphosphate (Fru-2,6-P₂), a potent phosphofructokinase activator and, therefore, glycolysis.¹²⁰ The synthesis and degradation of Fru-2,6-P₂ are catalysed by the homodimeric bifunctional enzyme PFK-2 (6-phosphofructo-2-kinase)/FBPase-2 (fructose-2,6-bisphosphatase), which is in turn is regulated by a cAMP-dependent protein kinase and a protein phosphatase 2A.¹²¹ Activation of the kinase stimulates gluconeogenesis by decreasing Fru-2,6-P₂, while phosphatase activation stimulates glycolysis by increasing Fru-2,6-P₂. Since Xyl-5-P is an allosteric activator of protein phosphatase 2A, this leads to a rapid increase in Fru-2,6-P₂, activation of phosphofructokinase, thereby activating glycolysis and inhibiting gluconeogenesis.¹²² Consistently, the infusion of xylitol during a combination of a pancreatic and hyperglycaemic clamp leads to a significant increase in Xyl-5-P.¹²³ Moreover, xylitol also causes a notable decrease in phosphoenolpyruvic carboxykinase mRNA in the liver, suggesting that Xyl-5-P may suppress gluconeogenesis through a direct transcriptional effect.¹²³ Xylitol was investigated as an osmotic agent replacing standard glucose-based PD solution in 6 insulin-dependent diabetic patients on PD therapy.¹²⁴ The therapeutic regimen, administered over a median duration of 8.7 months (range: 5–11 months), consisted of three daily exchanges of PD solution containing 1.5% xylitol and one exchange containing 3% xylitol. The total daily dose of xylitol delivered via the peritoneum was 150 g. Serum xylitol concentrations, measured after hypertonic exchange (3% xylitol), peaked at 86 ± 21 mg/dL (5.4 mM) 1-h post-exchange and decreasing sharply to 12 ± 5 mg/dL (0.8 mM) 3 h later. Using the 1.5% xylitol solution, serum xylitol concentrations reached lower peak levels of 35 ± 21 mg/dL (2.3 mM). Notably, these concentrations are significantly higher than the plasma concentrations reported by Witkowski et al.⁷ following ingestion of 30 g xylitol (0.629 mM) or used in their in vitro experiments (0.030 mM).⁷ They also exceed the plasma concentrations observed by Schneider et al.,¹¹¹ who reported levels of 3.4 mg/dL (0.233 mM) after administering 120 g of xylitol parenterally over 24 h.¹¹¹ The nearly 10-fold difference in plasma xylitol concentrations between Bazzato's study and Schneider's findings likely reflects differences in patient renal function.^111,124 The patients in Bazzato's study had no remaining kidney function, whereas those in Schneider's study retained renal clearance, which can efficiently eliminate excess xylitol. Additionally, the mode of administration differed: Bazzato's patients received xylitol-based PD solutions as boluses into the peritoneal cavity, while in Schneider's study, the xylitol-based solution was administered intravenously over an extended period rather than as a bolus. After 5 months of xylitol-containing PD treatment, patients in Bazzato's study showed a significant decrease in plasma triglycerides, total cholesterol, and inorganic phosphate levels compared with PD solution containing glucose alone. The exogenous insulin requirement was also reduced by up to 50%.¹²⁴ Still, it was also associated with a significant improvement in glycemic control: the percentage of glycated haemoglobin (%HbA1C) after 5 months of treatment with a stand-alone xylitol-based PD solution decreased from 12.9 ± 0.82% to 10.7 ± 1.08%. This antidiabetic action of xylitol-based PD treatment may be explained by the anti-gluconeogenic effect of the Xyl-5-P derived from liver exposure to peritoneal administration of xylitol.

In vitro data from various mesothelial and endothelial cell models has consistently shown that xylitol-based PD solutions have no pro-inflammatory, pro-angiogenic or pro-fibrotic effects compared with glucose-based or glucose-free PD solutions. Instead, they preserve mesothelial and endothelial cells' viability and membrane integrity.^125,126 Xylitol has even been shown to attenuate renal fibrosis by inhibiting bromodomain-containing protein 4 and its downstream transforming growth factor-β pathway.¹²⁷ In addition, PD patients treated daily with a PD solution containing a ternary combination of xylitol, glucose, and carnitine, where the final daily dose of xylitol was no more than 30 g, experienced no side effects, not even minor ones.¹¹⁵ Patients on PD have a high prevalence of CV complications and are at an increased risk of CV mortality. To make matters worse, if traditional CV risk factors such as age, IR, and diabetes mellitus, which are very common in these patients, were added, CV complications and mortality would increase exponentially.^98,128 All these considerations related to the parenteral route of chronic administration of xylitol in critically ill patients were not addressed in the recent publication discussing a potential link between xylitol and CV risk by Witkowski et al.⁷ nor by Beer and Allemann in their accompanying editorial.^7,129 Interestingly, the latter two authors misquoted a paper on xylitol's ability to enhance the anti-cancer effect of the chemotherapeutic drug 5-fluorouracil both in vitro and in vivo.¹³⁰ In line with a xylitol intervention even beyond the suggested bitterness in the above editorial, two more recent papers seem to confirm the potential anticancer effects of xylitol.^131,132

10. Summary/conclusion

The consumption of erythritol and xylitol stimulates the release of gastrointestinal satiation hormones while the impact on blood glucose and insulin concentrations remains minimal. These effects are desirable in the context of metabolic and CV health. The harmful effects of chronic overconsumption of conventional sugar are well-documented; hyperglycaemia negatively affects vascular health and promotes thrombocyte aggregation. Reducing glucose load—through dietary modifications or replacing glucose in PD—is important, and sugar alcohols might be helpful in reaching this goal. As a preventive measure, consuming erythritol and xylitol can improve oral health, and partially replacing table sugar with these sweeteners may also help in preventing weight issues and metabolic syndrome.

A potential short-term effect of xylitol and erythritol on ex vivo human platelet responsiveness has so far been shown in a small pilot trial. These findings need to be replicated in placebo-controlled studies with larger sample sizes and longer durations than 30 min after ingestion. Furthermore, long-term studies on regular consumption of higher amounts of sugar alcohols are lacking. Long-term RCTs focusing on isolated food items do not exist in nutrition research, as they are not practically feasible. Much of the evidence comes from observational studies, which show associations but cannot establish causality. Short-term studies (lasting weeks to a few months) are more feasible and well-designed interventional trials are needed. The mechanisms behind the upregulation of endogenous sugar alcohol production under certain conditions are not fully understood, and further research is necessary. Mendelian randomisation studies suggest that elevated plasma erythritol levels do not directly contribute to increased CV risk, but further carefully designed interventional trials are still warranted.

A general limitation of this review should be highlighted: while the cited studies originate from all continents, to the best of our knowledge, no comparisons have been conducted across different ethnic groups. Furthermore, as these studies were carried out in adults, the findings cannot be directly extrapolated to children.

Funding

B.K.W. is supported by the SNFS (Swiss National Science Foundation; Grants-No.: CRSII5_186346 and 320030E_189329) and the Botnar Foundation. A.C.M.-G. is supported by the SNFS (Swiss National Science Foundation; Grant-No.: 320030E_189329) and the Uniscientia Foundation. A.D. was supported by funds by the National Heart, Lung, and Blood Institute R01HL146442, R01HL149714, R01HL148151, and R01HL161004, by the National Institute of General Medical Sciences (NIGMS) RM1GM131968 and by the National Institute of Diabetes and Digestive and Kidney diseases (NIDDK) R01DK136945. M.B. receives funding support from the G. D’Annunzio University of Chieti-Pescara, Italy. V.M. receives funding support from the University of Padova, Italy MASO_BIRD2222_01. A.A.-S. is supported by the SNSF (Grant-No.: 310030_192635), a Novo Nordisk Access to Insight grant, the Innosuisse-Swiss Innovation Agency (114.430 IP-LS). G.D.L. was supported by Canadian Institutes of Health Research, ‘Cardiac Insulin Signalling in Diabetic Cardiomyopathy’ Project Grant—Principal Investigator; Canadian Institutes of Health Research, ‘Cardiac Energy Metabolism in HFrEF and HFpEF’ Project Grant—Principal Investigator; Canadian Institutes of Health Research, ‘Optimising Cardiac Energy Metabolism to Treat Heart Disease’ Foundation Grant—Principal Investigator; NIH R01 grant program, UofA ‘Role of mRNA-binding Protein Tristetraprolin in Cardiac mRNA Regulation and the Development of Heart Failure’ Operating Grant—Co-Investigator; Albert Einstein College of Medicine, ‘Mitochondrial ATP Synthase in Cardiac Biology and Disease’, Operating Grant—Co-Investigator. A.A., E.G., S.C., T.P. and M.G. report no funding.