Study examines the emerging science suggesting a link between calorie-free sweeteners and blood sugar control

Since the first introduction of saccharin, an array of artificial and other non-nutritive (i.e., low-calorie or calorie-free) sweeteners have become ubiquitous in the US food supply. However, a growing body of research suggests that these compounds are not inert in the body and may be disrupting our metabolism.

A new review and meta-analysis by researchers from the Food is Medicine Institute at the Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University, published in Current Atherosclerosis Reports, pulls together the best available evidence on how non-nutritive sweeteners affect health. Across 21 randomized clinical trials in adults, researchers observed that artificial and other low-calorie sweeteners, compared to non-caloric controls such as water or placebo, raised fasting insulin and HbA1c, a marker of long-term blood sugar control, and showed a trend toward worsening insulin sensitivity.

“What makes our analysis notable is that by focusing on non-caloric comparators, we better isolated the direct physiological effects of the sweeteners themselves, not the calories they replace,” said first author Meng Wang, a research assistant professor at the Friedman School of Nutrition Science and Policy. “When pooling findings from individual trials, we see signals that these compounds may have metabolic harms.”

One explanation based on the current evidence, the researchers say, involves the gut microbiome. Non-nutritive sweeteners generally pass through the gut and come into direct contact with these microbes. In one trial they reviewed that used detailed microbiome profiling along with experiments transferring microbes from humans to mice, certain low-calorie sweeteners were shown to alter both the composition and the function of the gut microbiota.

In addition to randomized trials, the researchers reviewed large observational studies, which generally found that consuming non-nutritive sweeteners is linked to a higher risk of developing cardiometabolic diseases. The team notes that these studies have limitations as people already at risk for these conditions may be more likely to choose these products. Different sweeteners may also have different health effects, so grouping them together may obscure the full picture. Taken together with the clinical trial findings, however, the researchers say that the overall body of evidence raises concern.

“The rapidly increasing use of these sweeteners has outpaced our understanding of their long-term health effects,” said study senior author Dariush Mozaffarian, a cardiologist and director of the Food is Medicine Institute. “Until we know more, caution is needed. If you’re replacing large amounts of added sugar in your diet, such as in multiple servings of soda, these low-calorie sweeteners may be a better alternative. But we can’t simply assume they are safe and innocuous, and avoiding them whenever possible appears a prudent choice.”

Finally, the researchers highlight a gap in U.S. labeling policy that hinders the research. Current regulations require manufacturers to list non-nutritive sweeteners in the ingredient list, but not the amount included. This makes it difficult for researchers to accurately assess non-nutritive sweetener intake and generate more definitive evidence about their health risk in large community or population studies.

The review underscores the need for additional carefully designed randomized controlled trials of both cardiometabolic risk factors and mechanistic pathways.

Complete information on authors, methodology and conflicts of interest is available in the published paper.