You may have seen a rash of media headlines like this one from CNN News recently:
Zero-calorie sweetener linked to heart attack and stroke, study finds
These headlines are based on a study published in Nature Medicine called “The artificial sweetener erythritol and cardiovascular event risk.”
Erythritol is a zero-calorie sweetener that is often used in low-carb and ketogenic diet products as a replacement for sugar. It’s popular amongst diabetics and others who are trying to limit their sugar and carbohydrate intake, so you can imagine the alarm this has caused in those communities.
On the surface, the findings of the study are certainly concerning. Researchers measured levels of erythritol in the blood and found that those with higher serum erythritol levels had an increased risk of stroke, heart attack, and death.
According to Dr. Hazen (from the CNN article above):
“If your blood level of erythritol was in the top 25% compared to the bottom 25%, there was about a two-fold higher risk for heart attack and stroke. It’s on par with the strongest of cardiac risk factors, like diabetes.”
Limited lab and animal research introduced in the paper suggest that erythritol may cause blood clotting, which is what then drives the increased cardiovascular risk.
Scary, right?
But don’t throw away your erythritol just yet.
There are three major problems with this study:
- The researchers did not measure erythritol intake. (They only measured erythritol in the blood.)
- Erythritol is a marker for a poor diet and metabolic dysfunction.
- We don’t yet know if high serum erythritol caused the increased cardiovascular risk, or was just associated with it.
Taken together, these issues prevent drawing any conclusions about whether consuming erythritol increases the risk of cardiovascular events or early death.
Let’s look at each of them in more detail.
The researchers did not measure erythritol intake
This study showed a correlation between serum levels of erythritol and cardiovascular events.
The media reports on this study, and even the researchers themselves, implied that erythritol consumption was the cause of elevated erythritol levels in the blood.
However, the researchers did not measure erythritol intake among the participants.
And there is good reason to believe that consuming erythritol was not the cause of the high serum erythritol levels observed in some of the participants.
Why?
Because erythritol wasn’t approved as a sweetener at the beginning of this study and was not widely used as the study progressed.
Two other large studies that showed an association between serum erythritol levels and cardiovascular or metabolic risk suffered from the same problem, as described in a 2023 review paper on erythritol:
Furthermore, in the two largest studies that showed these associations [79,80], sample collection occurred in the U.S. before erythritol was approved as a dietary component. Obviously, dietary erythritol intake does not explain the associations between circulating erythritol and cardiometabolic disease that were observed in these two studies. However, even for studies in which samples were collected after erythritol introduction into the food supply, it needs to be considered whether the global per capita production of erythritol, estimated at 0.023 g/day in 2019 [12,13], supports consumption levels high enough to obtain discernable associations with cardiometabolic disease. It seems unlikely.
Nutrients. 2023 Jan 1;15(1):204. doi: 10.3390/nu15010204
This almost certainly means that dietary erythritol was not the cause of elevated serum erythritol in the study participants.
Erythritol is a marker for a poor diet and metabolic dysfunction
If dietary erythritol wasn’t driving up blood erythritol levels in these participants, what was the cause?
A 2017 study found that humans produce erythritol endogenously (i.e. inside of our own bodies) in response to the consumption of both glucose and fructose via the pentose phosphate pathway (PPP).
A 2020 paper illustrated the conversion pathways:
Figure 1 from Curr Opin Clin Nutr Metab Care. 2020 Sep;23(5):296-301
Unlike erythritol, which was not widely available during the study in question, glucose and fructose are consumed in enormous amounts in both the U.S. and Europe.
So, it is far more likely that glucose and fructose consumption were driving the increase in serum erythritol levels.
What’s more, there is strong evidence that endogenous production of erythritol is correlated with cardiometabolic disease.
For example:
- The pentose phosphate pathway (PPP) has been shown to modulate insulin sensitivity and obesity-induced inflammation.
- Animal studies suggest a bi-directional link between high blood sugar and the PPP.
- The PPP is dysregulated in people with obesity and metabolic disease.
Given this, it seems likely that insulin resistance and high blood sugar (along with the over-consumption of glucose and fructose) are underlying causes of elevated serum erythritol levels.
Put another way, high levels of erythritol in the blood may simply be a marker for a poor diet and metabolic dysfunction.
I do want to note that the Nature Medicine study did include a small experiment where eight human participants were fed 30 grams of erythritol for seven days. Their serum levels of erythritol increased significantly, but the significance of this is unclear because no markers of blood clotting were measured and no adverse effects were noted.
We know that high serum erythritol levels are associated with a higher risk of cardiac events and death. And we know that consuming erythritol increases serum erythritol levels. So, it’s tempting to assume that consuming erythritol increases the risk of cardiac events and death.
But that is not a safe assumption, because correlation is not causation.
We don’t yet know if high serum erythritol caused the increased cardiovascular risk, or was just associated with it
Tell me if this sounds familiar:
- Consuming saturated fat increases serum cholesterol levels.
- High cholesterol levels are associated with a higher risk of heart attacks.
- Therefore, eating saturated fat increases the risk of a heart attack.
This faulty reasoning was so deeply ingrained in our culture and scientific establishment that it wasn’t seriously questioned until a couple of decades ago.
Since then, we’ve learned that consumption of saturated fat is not convincingly linked to an increased risk of heart attacks, and in fact, may decrease the risk of other cardiovascular events like stroke. (If this is news to you, see this article.)
The mistake researchers made was assuming that the intermediary marker—in this case, cholesterol—played a causal role. But we now have reason to believe that high cholesterol is more of a marker of underlying cardiovascular dysfunction, and it is that dysfunction that drives the risk of heart attacks.
It’s possible that the same mistake is being made here.
The authors of the Nature Medicine paper have posed this hypothesis:
- Consuming erythritol increases serum erythritol levels.
- High serum erythritol levels are associated with a higher risk of cardiac events.
- Therefore, consuming erythritol increases the risk of cardiac events.
However, their study lacks key information to support this hypothesis.
We know that erythritol can be produced endogenously in response to fructose and glucose consumption.
We know that insulin resistance, high blood sugar, and oxidative stress (all features of metabolic dysfunction) increase serum erythritol levels.
And we know that consuming erythritol increases levels of erythritol in the blood.
But we don’t know that high erythritol levels in the blood are causing an increased risk of cardiac events and death.
Consuming saturated fat increases serum cholesterol levels in a substantial percentage of people, but we now know that (on average) this doesn’t lead to an increase in cardiovascular risk.
In cases where high cholesterol is associated with a higher risk of heart attacks, it is likely that cholesterol is a marker for another underlying factor that is driving the increased risk.
The same may be true with the relationship between dietary erythritol and serum erythritol. High levels of erythritol in the blood may be a risk factor when they reflect underlying metabolic dysfunction and/or high sugar intake, but not when they reflect consumption of erythritol in the diet.
This is one of the key questions that future research needs to answer.
It’s worth noting that in studies where animals were fed erythritol, serum erythritol levels increased but no adverse effects were noted.
For example, in this study, mice were fed erythritol for eight weeks. While their plasma erythritol levels increased by 20–60 fold compared with the control group, there were no differences in body weight, adiposity, or glucose tolerance between the groups.
In a study where rats consumed a 10% erythritol diet for two years, researchers observed positive effects on body weight with no adverse changes on numerous biomarkers related to metabolic health.
Conclusions
The only thing we can conclude with certainty from the Nature Medicine study is that there is a strong correlation between serum erythritol levels and cardiovascular events and mortality.
That’s it.
It does not tell us that high serum erythritol causes cardiac events or death.
Nor does it suggest that consuming erythritol in the diet increases the risk of cardiac events or death.
In fact, given prior research, there is reason to believe that serum erythritol is simply a marker for sugar intake and/or underlying metabolic dysfunction, and is not driving the increased cardiovascular risk observed in people with high levels of erythritol in their blood.
But we can’t be sure of that, either.
It’s possible that consuming erythritol in significant amounts may lead to undesirable outcomes.
What I’m saying here is that we need more research to determine whether this is the case. The Nature Medicine study does not shed light on this question—despite the claims being made in the media.