“So sweet was ne’er so fatal. I must weep, But they are cruel tears. This sorrow’s heavenly, It strikes where it doth love.”

― William Shakespeare, Othello Act 5, Scene 2, 17–22

All of us have, at one time or another, likely received a text or an email IN ALL CAPITAL LETTERS. If you’re anything like me, you may have found it particularly annoying and may have even whispered under your breath, “Stop shouting at me!” Communication is a nuanced thing, whether it be a text message, a conversation, or the mating moonwalk of the red-capped manakin (Ceratopipra mentalis). It’s not just about letters or even the presence of words but more about information, context, and the deciphering of meaning.

The process is the same, be it a lover’s sweet whisper or a biochemical signal. That slowly spoken, scented sentence, in fact, sets in motion a physiologic cascade of irrational cacophony, as any parent of a heart-struck teenager can attest.

What happens at the cellular level when we do the same?

Xylitol is a sugar alcohol that naturally occurs in small amounts within the human body as a byproduct of normal everyday glucose metabolism. Under typical circumstances, the xylitol levels in human blood are very low, ranging from about 0.03 to 0.06 milligrams per deciliter (mg/dL). The total production of xylitol in the human body is estimated to be no more than about 15 grams per day, depending on various factors, including diet and overall metabolism.

But for many, unfortunately, that’s not the average. Xylitol belongs to a class of nonnutritive and low-calorie sweeteners, commonly referred to as ‘artificial sweeteners,’ that are ubiquitous in ultra-processed foods. Thanks to the promotion by organizations such as the American Heart Association, the American Diabetes Association, and other diabetes associations around the world, the use of such artificial sweeteners has significantly increased over the last several decades. Because xylitol can be cheaply produced from microbial and enzymatic fermentation of wood and agricultural waste, it has become increasingly prevalent as a preferred sweetener in a variety of manufactured food products. Since it approximates the sweetness level of common table sugar (sucrose), it can be used as a 1:1 sugar substitute resulting in single servings as large as 45 g. This week’s study examined the cardiovascular risk associated with such consumption.

The Study:

  • The study utilized a combination of in vivo and in vitro analyses.
    • There was a discovery cohort of 1,157 human subjects that identified the presence of a five-carbon sugar in those at risk of cardiovascular events.
    • There was a validation cohort of 2,149 human subjects utilized to confirm that the five-carbon sugar was indeed xylitol.
    • A mouse model was utilized to examine the effects of xylitol on platelet responsiveness and thrombus formation in vivo.
    • There was an active intervention study of 10 healthy humans used to assess the effects of xylitol consumption on in vivo xylitol levels and platelet function
  • The study examined the risk for major adverse cardiovascular events (MACE), which was composed of myocardial infarction (heart attack), stroke, or death.
  • There was no difference in outcomes according to biological sex.

The Take-Away:

  • The mechanistic studies demonstrated that xylitol increased platelet reactivity through a variety of mechanisms.
  • The human intervention study demonstrated that the xylitol concentrations associated with increased platelet activity and thrombus formation were achieved with the consumption of typical daily intake amounts.
  • The human intervention study showed thousand-fold increases in plasma xylitol levels 30 minutes after ingesting 30 grams of xylitol dissolved in water.
  • The highest consumers of xylitol (third versus first tertile) experienced a 57% increased risk of a major adverse cardiovascular event within three years.

The Caveat:

Xylitol is a five-carbon sugar alcohol that is naturally produced by humans in the liver in small amounts. It also naturally occurs in very small amounts in fruits such as strawberries, raspberry, bananas, and yellow plums, and vegetables such as cauliflower, spinach, carrots, onions, white mushrooms, eggplant, lettuce, and pumpkins. Xylitol is formed naturally in the human body as part of the process of protecting cells against oxidative stress and generating ribose-5-phosphate, which is required for nucleotide and nucleic acid synthesis.

Due to its low glycemic index (xylitol has a G.I. of 7 compared to sucrose which has a G.I. of 65) and insulin-independent metabolism, xylitol has been promoted by many professional organizations, such as the American Heart Association, the American Diabetes Association, and other diabetic associations worldwide, as a sugar substitute in diabetic diets. It is lower in calories than sucrose (xylitol delivers approximately 2.4 cal per gram compared to 4 cal per gram for sucrose) but has approximately the same sweetness level and, therefore, is generally used as a 1:1 replacement for common table sugar. For example, if a cake recipe called for 100 g of sugar, that would be replaced by 100 g of xylitol. That product may then be marketed as a lower-calorie and sugar-free version. Additionally, since xylitol is naturally occurring and produced by the human body, it is also often advertised as a “natural” sweetener.

The Food and Drug Administration (FDA) approved xylitol in the same manner as many other food additives: through the GRAS, Generally Recognized As Safe, pathway. The FDA currently considers xylitol safe for use in foods and it remains approved as a direct food additive. The European Food Safety Authority (EFSA), which lists xylitol as E 967, currently classifies it as “reevaluation ongoing.”

If additional studies replicate the findings here, it confirms a disturbing trend. For decades, the scientific community has backed the promotion of such sweeteners as a preventative and therapeutic modality to treat obesity. The use of such non-sugar sweeteners (NSS), low-calorie sugars, and sugar alcohols (polyols) has also been promoted as part of a dietary solution for type II diabetes and cardiovascular disease and as part of a solution for improved general health.

Aggressive marketing from industrial food producers has furthered the push to consumers by labeling such sweeteners as ‘natural’ and ‘naturally derived’ (as they can be extracted from berries, oats, sugarcane bagasse, and corn husks) to imply an added level of safety and benefit. The xylitol market was worth US$701.3 million in 2023, and the forecasts are for continued aggressive growth. All this despite limited data on long-term or high-dose use.

A similar endogenous sugar alcohol, erythritol, has recently been both clinically and mechanistically linked to cardiovascular disease.[1] The use of such sweeteners has reached the point where they can now be detected within groundwater and waste effluent. They have become so pervasive that their detection and quantification have been recommended as “ideal chemical markers of domestic wastewater in groundwater.”[2] Adding this study to the growing repository of data on the effects of these compounds at physiologically relevant doses should give pause in recommending them to anyone, let alone those at particularly increased cardiovascular risk, such as those with obesity, diabetes, and known cardiovascular disease.

Temptation by endless sweeties with the promise of nary a consequence was the downfall of many a fairytale hero. Ignoring such lessons of youth may lead us, as The Bard observed, to a sweet fatale!

[1] (Witkowski, 2023)

[2] (Buerge, 2009)


Marco Witkowski, Ina Nemet, Xinmin S Li, Jennifer Wilcox, Marc Ferrell, Hassan Alamri, Nilaksh Gupta, Zeneng Wang, Wai Hong Wilson Tang, Stanley L Hazen, Xylitol is prothrombotic and associated with cardiovascular risk, European Heart Journal, 2024; ehae244, https://doi.org/10.1093/eurheartj/ehae244.

Additional Resources:

Buerge IJ, Buser HR, Kahle M, Müller MD, Poiger T. Ubiquitous occurrence of the artificial sweetener acesulfame in the aquatic environment: an ideal chemical marker of domestic wastewater in groundwater. Environ Sci Technol 2009;43:4381–5. https://doi.org/10.1021/es900126x.

Gardner C, Wylie-Rosett J, Gidding SS, Steffen LM, Johnson RK, Reader D, et al. Nonnutritive sweeteners: current use and health perspectives: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation 2012;126:509–19. https://doi.org/10.1161/CIR.0b013e31825c42ee.

Johnson RK, Lichtenstein AH, Anderson CAM, Carson JA, Després JP, Hu FB, et al. Low-calorie sweetened beverages and cardiometabolic health: a science advisory from the American Heart Association. Circulation 2018;138:e126–40. https://doi.org/10.1161/CIR.0000000000000569.

Milgrom P, Rothen M, Milgrom L. Developing Public Health Interventions with Xylitol for the US and US-Associated Territories and States. Suom Hammaslaakarilehti. 2006 May 15;13(10-11): 2-11.

Precision Business Insights. Xylitol Market. https://www.precisionbusinessinsights.com/ market-reports/xylitol-market?trk=article-ssr-frontend-pulse_little-text-block. 2023.

Umai D, Kayalvizhi R, Kumar V, Jacob S. Xylitol: bioproduction and applications-a review. Front Sustainability 2022;3. https://doi.org/10.3389/frsus.2022.826190

Witkowski M, Nemet I, Alamri H, Wilcox J, Gupta N, Nimer N, et al. The artificial sweetener erythritol and cardiovascular event risk. Nat Med 2023;29:710–8. https://doi.org/10.1038/s41591-023-02223-9.

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