Trending Clinical Topic: Artificial Sweetener Safety

Ryan Syrek


March 10, 2023

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New developments in the so-called sugar-free paradox have further called into question whether artificial sweeteners represent a healthy way to cut calories or a potentially dangerous option. Recent findings have explored connections between various sugar alternatives and cardiovascular health risks and anxiety, among other concerns.

Perhaps most notably, a recent multi-part study found that one particular option resulted in increased 3-year risk for significant heart conditions. The study had three main parts. First, in 1157 patients undergoing cardiac assessment, researchers found that high erythritol levels were associated with increased risks. These findings were then reproduced in two large populations in two different regions (see Infographic).

Researchers also found that adding erythritol to whole blood or platelets led to clot activation. Separately, they also found that ingesting 30 g of an erythritol-sweetened drink—comparable to a single beverage can or pint of keto ice cream—induced marked and sustained (< 2 days) increases in levels of plasma erythritol in eight healthy volunteers. The issue remains controversial because some experts point out that erythritol can be made inside the human body and that intake in most people's diets is typically low. However, senior author Stanley L. Hazen, MD, PhD, points out that 2013-2014 National Health and Nutrition Examination Survey data show that daily intake of erythritol is estimated to reach 30 g/d in some individuals.

This isn't the first time an artificial sweetener has been linked to cardiovascular disease. A large-scale, prospective study of French adults published last September found that total artificial sweetener intake from all sources was associated with increased overall risk for cardiovascular and cerebrovascular disease. The study included 103,388 French adults from the NutriNet-Sante cohort, of whom, 37.1% reported consumption of artificial sweeteners. The sugar substitutes assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%).

Over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk for cardiovascular or cerebrovascular events. These included myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% CI, 1.01-1.18; P = .03).

Average intake was 42.46 mg/d among consumers, which corresponds to about one individual packet of tabletop sweetener or 100 mL of diet soda. The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person years vs 314 per 100,000 person years in nonconsumers. Aspartame intake was particularly associated with increased risk for cerebrovascular events, whereas acesulfame potassium and sucralose were associated with increased coronary heart disease risk.

Aspartame was also recently associated with increased risk for anxiety in a preclinical study involving mice. Researchers observed that mice that drank water with aspartame showed pronounced anxiety-like behaviors in maze tests. This occurred at doses equal to less than 15% of the maximum daily human intake recommended by the US Food and Drug Administration. Aspartame exposure also resulted in changes to the expression of genes that affect the amygdala, a brain region that regulates anxiety and fear. The administration of diazepam, which is used to treat generalized anxiety disorder, alleviated the anxiety behavior in the mice.

These and other similar studies leave clinicians in a difficult position. In responding to the erythritol study, F. Perry Wilson, MD, MSCE, notes that he is "not terribly worried right now about my monkfruit sweetener, or my sugar-free gum, or my toothpaste. While the harms from sugar substitutes are still mostly theoretical, the harms of sugar are all too real." His conclusion that erythritol may be the "lesser of two evils" is based on well-established conclusions about sugar-sweetened products that contain material like high-fructose corn syrup. Sugary beverages have been linked to colorectal cancer, inflammatory bowel disease, nonalcoholic fatty liver disease, and others.

For some experts, the best advice is to employ moderation all around, avoiding excess sugar and artificial sweeteners. Embracing simple, proven advice, like drinking more water and less processed beverages, may be the best strategy. However, the popularity of this week's top trending clinical topic may suggest that people are still quite interested in hearing just what the evidence has to say about sugar alternatives.

Take a quiz about recent research involving artificial sweeteners.


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