By Dr. Ryan Lowery and Dr. Jacob Wilson

Some of you have seen the latest article from news outlets regarding a publication (Witkowski et al. 2023) that indicates that “circulating levels of erythritol were associated with incident adverse cardiovascular event risk independent of traditional CVD risk factors.”  Since we use erythritol as a sweetener in some of our products, we wanted to address this topic and take the time to highlight some very important points so that you have the full trust in our products and the science we use to drive our decisions.

First, we want to highlight some specific findings.  The researchers looked at levels of erythritol in the blood of an elderly population of subjects with metabolic dysregulation (overweight, 22 % diabetes, 72 % hypertension, 76 % coronary artery disease, and 17 % heart failure) and found a correlation between erythritol in the blood and increased risk of cardiovascular events.  This means that people who had higher levels of erythritol in the blood tended to have higher rates of cardiovascular events.  Second, they looked in cell culture (petri dish) and animal models and found a trend for increasing platelet aggregation with increasing levels of erythritol.  For the animal model, these researchers injured the common carotid artery (delivers blood to the brain) and injected them with erythritol (25 mg/kg) which is not an accurate representation of what happens during normal physiology and consumption of erythritol within products.   That being said, there are some important things to note.

Correlation does not equal causation.  Higher levels of erythritol in the blood does not mean consuming erythritol causes these problems (more on that later).  In fact, your body actually makes erythritol on its own in the presence of glucose (sugar).  Erythritol has been shown to be synthesized endogenously from glucose via the pentose-phosphate pathway (PPP) and through in vivo conversion of erythritol to erythronate in stable isotope-assisted dried blood spot experiments (Hootman et al. 2017).   Thus, our body’s own production of erythritol from glucose may contribute to the association between erythritol, obesity, and any cardiovascular complications.  Further, it is essential to understand that nutrients and/or metabolites in the blood are often a sign of a dysfunctional metabolism (metabolic dysregulation).  For example, uncontrolled diabetics often will register with very high ketones levels (AKA ketoacidosis) which led people to believe that a state of ketosis was dangerous.  However, ketosis is induced from athletics (healthy), diet (healthy), fasting (healthy), and supplementation (healthy).  We can name numerous other examples of elevated substances in diseased elderly populations, but suffice it to say this makes the distinction between correlation and causation.

Additionally, we must look at and understand physiological ranges of this “platelet aggregation” and understand the limitations around this study design.  For one, this study used an in vitro model (in a test tube) and saw that cells bathed with erythritol increased markers of platelet aggregation.  It is very difficult to draw conclusions from cell culture models on platelet aggregation.  For example, the preponderance of evidence available demonstrates that platelet aggregation and function are increased with exercise, even in the presence of aspirin (El-Sayed et al. 2005).  However, the overwhelming consensus is that exercise has tremendous cardiovascular benefits.  This is an example of why generalizing from a cell culture model to chronic changes over time should always be done with extreme caution.  For these reasons, toxicity trials on a substance must remain the gold standard.

In fact, the toxicity and carcinogenicity of diets containing a human equivalent of 70 + grams daily of erythritol did not affect the survival of rats when given for the majority of their lives and showed no signs of nephrotoxicity, tumor-inducing or tumor-promoting changes or negative effects in any organs (lina et al. 1996).  Beyond the excellent safety profile, scientists suggest that erythritol can counter one of the major mechanisms of cardiovascular disease in diabetics, which is impaired blood vessel function.  In science terms, we call this endothelial function.  The endothelium is the inner lining of blood vessels and is responsible for their ability to constrict and dilate. They do this by releasing signaling molecules like nitric oxide, which under conditions of chronically elevated glucose is impaired. Research in animals has shown that erythritol can help prevent the impaired endothelial function that occurs in diabetic rats (den Hartog et al. 2010). It is thought that this may be related to erythritol’s antioxidant effects (Yokozawa et al. 2002), as we know oxidative stress increases with impaired glucose tolerance (Yokozawa et al 2002).

These cardiovascular benefits were recently demonstrated in a human study (Flint et al. 2014) which had individuals at high risk for cardiovascular disease (type II diabetics) consume 36 grams of erythritol per day for 4 weeks and a single dose of 24 g during the baseline and final visits. These scientists found that a drink of erythritol improved endothelial function right away as measured by fingertip peripheral arterial tonometry.   Long term erythritol decreased central pulse pressure and tended to decrease carotid-femoral pulse wave velocity. Thus, erythritol consumption acutely improved small vessel endothelial function, and chronic treatment reduced central aortic stiffness. Again, this demonstrates positive cardiovascular effects of erythritol.  It may be that mechanistically the body’s conversion of glucose to erythritol may be a way to counter the cardiovascular risk caused by insulin resistance.  However, this remains to be examined. The authors concluded that erythritol may be a preferred sugar substitute for patients with diabetes mellitus. Further, new studies published in 2023 have demonstrated the clear safety of erythritol and even talk further about its possible benefits (Teysseire et al. 2023 & Mazi and Stanhope, 2023).  For this reason, the United States Food and Drug Administration and has given Erythritol GRAS status (Generally Recognized as Safe) and along with the European Food and Safety Administration has approved it for as non-nutritive sweetener, flavor enhancer, stabilizer, and thickener in a variety of foods such as bakery fillings, cakes and cookies, frozen dairy desserts, puddings, yogurt, chewing gum, candies, and reduced and low-calorie beverages (USDA GRAS Notices 208, 297, and 382).

Beyond this, Pruvit has performed extensive safety research on our products.  We have published two extensive safety studies using multiple servings of our ketones.  In a 2020 study (Stefan et al. 2020) scientists gave healthy adults 3 servings worth of Pruvit ketones for 3 months.  These researchers found no negative changes in any indicators of kidney, liver, or comprehensive metabolic panel examinations.  In addition, there were no changes in automated differential cell count, complete blood count, and hemoglobin A1c.  Finally, the product did not change any cardiovascular risk factor including resting blood pressure and heart rate or negatively impact psychological surveys over the time period.  The scientists concluded that this study established the safety of long term BHB supplementation.  Moreover, while Pruvit does not market its products to adolescents, these scientists (Stefan et al. 2021) conducted a more recent study on the safety of ketones (sweetened with erythritol) on adolescents as well and found no negative effects in any of the parameters previously discussed when administered over several weeks.

As a company, Pruvit will continue to lead with education while always keeping the safety of its community at the forefront of its mission to become better versions of ourselves. Thank you to our team of scientists, our scientific council, and our entire product development team for not only continuing to keep Pruvit at the forefront of innovation, but to help provide safe and effective products for our community.

References:
den Hartog GJ, Boots AW, Adam-Perrot A, Brouns F, Verkooijen IW, Weseler AR, Haenen GR, Bast A (2010) Erythritol is a sweet antioxidant. Nutrition 26:449–458. doi: 10.1016/j.nut. 2009.05.004

El-Sayed, M. S., Ali, N., & Ali, Z. E. S. (2005). Aggregation and activation of blood platelets in exercise and training. Sports medicine, 35, 11-22.

Flint, Nir et al. “Effects of erythritol on endothelial function in patients with type 2 diabetes mellitus: a pilot study.” Acta diabetologica vol. 51,3 (2014): 513-6. doi:10.1007/s00592-013-0534-2

Hootman, Katie C., et al. “Erythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults.” Proceedings of the National Academy of Sciences 114.21 (2017): E4233-E4240.

Lina, B A et al. “Chronic toxicity and carcinogenicity study of erythritol in rats.” Regulatory toxicology and pharmacology: RTP vol. 24,2 Pt 2 (1996): S264-79. doi:10.1006/rtph.1996.0108

Mazi, Tagreed A., and Kimber L. Stanhope. “Erythritol: An In-Depth Discussion of Its Potential to Be a Beneficial Dietary Component.” Nutrients 15.1 (2023): 204.

Stefan, Matthew, et al. “The effects of exogenous beta-hydroxybutyrate supplementation on metrics of safety and health.” Int. J. Nutr. Food Sci 9 (2020): 154-162.

Stefan, Matthew, et al. “The effects of exogenous beta-hydroxybutyrate supplementation on metrics of safety and health.” Int. J. Nutr. Food Sci 9 (2020): 154-162.

Teysseire, Fabienne, et al. “Metabolic Effects and Safety Aspects of Acute D-allulose and Erythritol Administration in Healthy Subjects.” Nutrients 15.2 (2023): 458.

Yokozawa T, Kim HY, Cho EJ (2002) Erythritol attenuates the diabetic oxidative stress through glucose metabolism and lipid peroxidation in streptozotocin-induced diabetic rats. J Agric Food Chem 50:5485–5489

US Food and Drug Administration. GRAS Notice 297: Erythritol Fatty Acid Esters. 2009. Available online: https://www.cfsanappsexternal.fda.gov/scripts/fdcc/index.cfm?set=GRASNotices&id=297&sort=GRN_No&order=DESC&startrow=1&type=basic&search=erythritol (accessed on 15 January 2022).

US Food and Drug Administration. GRAS Notice 208: Erythritol. 2006. Available online: https://www.cfsanappsexternal.fda.gov/scripts/fdcc/index.cfm?set=GRASNotices&id=208&sort=GRN_No&order=DESC&startrow=1&type=basic&search=erythritol (accessed on 15 January 2022).

US Food and Drug Administration. GRAS Notice 382: Erythritol. 2011. Available online: https://www.cfsanappsexternal.fda.gov/scripts/fdcc/index.cfm?set=GRASNotices&id=382&sort=GRN_No&order=DESC&startrow=1&type=basic&search=erythritol (accessed on 15 January 2022).

Witkowski, Marco, et al. “The artificial sweetener erythritol and cardiovascular event risk.” Nature Medicine (2023): 1-9.