Xylitol: an unnatural natural sweetener

 

A recent study found that the “artificial sweetener” xylitol was associated with increased thrombosis and cardiovascular risk (see xylitol assoc with thrombosis and cardiovasc risk EurHeartJ2024 in dropbox, or  doi.org/10.1093/eurheartj/ehae252)

 

Details/Results (will review the various aspects of the study independently):

-- untargeted metabolomics (metabolomics involves studying a set of metabolites present within an organism that may be involved with development of the disease), in the initial discovery cohort:

    -- evaluation of the plasma from 1157 sequential stable subjects undergoing elective diagnostic cardiac evaluations found that the presence of the chemical C₅H₁₂O₅ was associated with the incident major adverse cardiovascular events (MACE) of MI, stroke or death over a three-year period

    -- a more selective analysis subsequently showed that this C₅H₁₂O₅ chemical was xylitol

    -- subjects with increased levels of this chemical had poor event-free survival and significant increased risk for incident MACE that tracked with the quantity of xylitol present

 

-- stable isotope dilution mass spectrometry in specific analyses of xylitol in a more robust quantitative way in a validation cohort:

    -- 2149 subjects undergoing elective diagnostic cardiac evaluation documented that higher plasma levels of xylitol were again observed among subjects who experienced MACE, also in a dose-dependent manner (i.e. those with higher plasma xylitol levels had significantly increased risk of incident 3-year MACE, even after adjusting for traditional cardiovascular risk factors and hsCRP levels, with adjusted hazard ratio of 1.06 (1.01-1.11), p=0.023

    -- in addition there was an 80% increased risk of incident thrombotic events, aHR 1.80 (1.05-3.08), p=0.03

    -- the above association between xylitol and MACE was found in all subgroups analyses, including level of renal function and those on antiplatelet drugs

 

-- examination of postprandial circulating levels of xylitol following ingestion of a xylitol-sweetened drink:

    -- plasma levels in both the discovery and validation cohorts were monitored after an overnight fast of at least 12 hours:

        -- baseline xylitol levels were 0.30 (0.27-0.34) μM [there is this normal small baseline endogenous production of xylitol in the human body]

        -- 30 minutes after ingestion of 30 g of xylitol-sweetened water (an exposure comparable to a pint of numerous xylitol-sweetened ice creams or bakery goods or candy), there was more than a 1000-fold increase in plasma levels of xylitol, with a median of 312 (134-629) μM. These levels return to low micromole levels within 4 to 6 hours, with a plasma half-life of about 13 minutes (apparently returning to the levels of xylitol endogenous production)

 

-- platelet responsiveness to physiologic levels of xylitol (levels observed after an overnight fast):

    -- no effect by incubating platelet-rich plasma from healthy volunteers with a physiologic (endogenous)  level of xylitol (30 μM) in the presence of submaximal levels of known platelet aggregation agonists (both adenosine diphosphate and thrombin receptor activator peptide-6, aka ADP and TRAP-6)

    -- but there was a dose-dependent response to increasing levels of xylitol, up to 300 μM

    -- just to be sure that the platelet aggregation was specifically from the platelets and not other factors besides a direct interaction with platelets, they repeated this study with isolated washed human platelets from healthy volunteers, again finding a dose-dependent enhancement of platelet activation

 

-- effect of xylitol on platelet clotting in whole blood and thrombosis potential in vivo:

    -- xylitol substantially accelerated the rate of collagen-dependent platelet adhesion and spreading under physiologic sheer force

    -- mice with elevated plasma levels of xylitol had marked increases in the rate of clot formation and a significant reduction in the time to cessation of blood flow following arterial injury

 

-- other indices of platelet reactivity associated with dietary xylitol in humans:

    -- in a dose-dependent fashion, platelet functional analyses found that xylitol exposure provoked a multiple-fold increase in aggregation responses to either ADP or TRAP-6 at all doses examined

 

 

Commentary:

-- xylitol is similar to sucrose, is pretty much equal to the sweetness of sucrose (i.e. one can substitute one teaspoon of xylitol for 1 teaspoon of sucrose), but has fewer calories (2.4 kcal per gram versus 4 kcal per gram). It is sold in bulk similar to sugar

-- xylitol has caught on remarkably well industrially: $701.3 million in 2023 with annual growth expected to be greater than 4%

-- in addition to gum, candies, baked goods, ice cream, and peanut butter, xylitol may be found in toothpaste, mouthwash, jams and jellies, power drinks, condiments, cosmetics, face cream, and hair care products

    -- xylitol has been found to be associated with increased bone strength, decreased skin permeability,  and increased skin moisture (it is therefore used in cosmetics)

    -- xylitol is also used for tooth protection (it is associated with significantly fewer dental caries vs sucrose) and may be associated with fewer respiratory infections (sinusitis, otitis, rhinitis)

 

-- xylitol is a five-carbon sugar alcohol that is found naturally in small quantities in fruits and vegetables. xylitol is also produced endogenously in the human body as noted above, but the concern regarding the adverse events documented above is that it has 1000-fold higher blood levels when ingested as an additive

 

-- of course, one of the concerns of this study is the sweeteners such as xylitol are specifically recommended for people who have obesity, diabetes, and cardiovascular disease per the American Heart Association and various diabetes associations around the world, exactly the groups likely to have the most adverse cardiovascular events anyway and likely more so with xylitol

-- the history of artificial sweeteners is also not so sweet: several artificial sweeteners are associated with insulin resistance, type II diabetes, and cardiovascular disease, as well as having negligible effects on weight loss

-- it should be noted that there are huge species differences in the effects of xylitol: dogs who eat xylitol  can die from hyperinsulinemia hypoglycemia from the xylitol (for example, it is commonly used as an additive to peanut butter, for example, which seems to be an attractant to many dogs)

 

-- in general, artificial sweeteners have generally been seen as having safe status (GRAS: ”generally recognized as safe”) by both the FDA and the European Union, though the World Health Organization in its May 2023 recommendations "advised against the use of non-sugar sweeteners for weight control" as mentioned in the xylitol article (though the editorialists for the article comment that these recommendations actually do not apply to “low-calorie sugars “and sugar alcohols (polyols), since these are sugar derivatives that contain calories (see Beer, JH and Alleman M. Eur Heart J (2024) 00, 1-3; doi.org/10.1093/eurheartj/ehae252)

    -- the family of polyols include sorbitol, xylitol, lactitol, mannitol, erythritol and maltitol

    -- these polyols are “not sugar-free sweeteners “or “natural” as they are often marketed; nor are they harmless just because they can be extracted from berries, oats, birch, sugarcane, and corn husk

    -- erythritol, a related polyol, has also been found to be associated with both the pro-thrombotic effects as well as increased major adverse cardiovascular events as xylitol, in a study done by the same researchers as in the xylitol study above

        -- would be useful to know if the other polyols have similar associations....

 

-- As a prospective here, it is important to realize that sugar itself is associated with an increase in cardiovascular events, including stroke and heart attack (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10910551/ ). we do not know whether the increased adverse effects found with xylitol are actually much higher than that involved with eating more sugar.

-- And, we do know, in the United States most adults consume 10% or more of their calories from added sugar and approximately 10% of people consume 25% or more if their calories from sugar, as assessed in a study from  2005-2010

    -- the Institute of Medicine did recommend at that time that added sugar make up less than 25% of total calories, though the WHO recommended less than 10%. the AHA now recommends limiting added sugars to no more than 6% of calories each day https://www.heart.org/en/healthy-living/healthy-eating/eat-smart/sugar/added-sugars

    -- in assessing the role of xylitol as a food additive, it would be very helpful to know if plain sugar is associated with MACE and thromboses as found with xylitol, and, if so, is there a dose-response relationship?? Which is the healthier of the 2?

 

Limitations:

-- the randomized controlled trials on artificial sweeteners have typically been conducted over a short period of time and do not reflect real-life exposures, limiting their ability to assess long-term concerns

-- we do not have head-to-head comparisons of sugar with xylitol, to see if one has fewer adverse effects than the other; without this, it is hard to have a global recommendation

 

so, what is to be done?

-- perhaps we really should be attuned to the warning that the writer and nutrition guru Michael Pollan said: "don't eat anything your great grandmother wouldn't recognize as food" when looking at the list of ingredients 

-- many food additives have potentially severe consequences (and have not been rigorously tested). for example, emulsifiers (used to make mayonnaise, ice cream, chocolates, cookies, creamy sauces, margarine, or peanut butter in order to prevent separation of oil vs water and thereby create a smooth homogeneous texture) can also attack the mucous barrier in the colon (allowing for more absorption of toxins), microbiome changes, and increased inflammation (including worsening of IBD symptoms)

-- overall, non-nutritive sweeteners are associated with significant cardiovascular events and weight gain: https://gmodestmedblogs.blogspot.com/2020/11/cardiovasc-disease-inc-with-sweet.html

-- and it is important health-wise to decrease sugar consumption in general. Decreasing sugar consumption can lead to increased sweetnness sensitivity to food (ie, eating less sugar overtime can make the smaller amounts of sugar ingested make the food taste sweeter)

-- which really means that the healthiest diets are the ones with the fewest additives, substitutions, use of non-natural ingredients, etc.  It is certainly not an easy task to eliminate these foods completely, though decreasing soda and juice consumption is a good start. But this is an increasingly difficult task given the huge structural issues: lots of enticing advertising by the food industry, adverse location of healthier products in grocery stores, food desserts in the inner city and rural areas, high cost of healthy foods vs energy-dense fast foods, lack of accessibility to  locally-grown healthy vegetables/fruits, and even a huge shrinkage in the numbers of people who cook their own food (as the popular cooking shows have morphed more into competitive sports than sharing cooking skills)

 

geoff

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