“Zero sugar” can sound simple. If a food or drink has little or no sugar, it may seem like the obvious better choice for blood sugar, weight or overall health.
But a new review and meta-analysis from researchers at Tufts University suggests the story is more complicated. The paper, published in Current Atherosclerosis Reports, found signs that artificial and other nonnutritive sweeteners may not be biologically inactive, especially when they are compared with water or placebo rather than sugar-sweetened foods and drinks.
The review does not show that low-calorie sweeteners are worse than added sugar. It also does not prove that any one sweetener causes diabetes, gut problems or metabolic disease. Instead, it points to a more careful conclusion: calorie-free does not necessarily mean effect-free.
The researchers reviewed evidence on nonnutritive sweeteners, a category that includes artificial and other low-calorie or calorie-free sweeteners used in many diet drinks, zero-sugar products, gums, protein foods, yogurts and other packaged items.
Across 21 randomized clinical trials in adults, the researchers found that nonnutritive sweeteners, when compared with noncaloric controls such as water or placebo, were linked with higher fasting insulin and HbA1c, a marker of longer-term blood sugar control. The analysis also found a trend toward worse 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.”
That comparison is important. A diet soda may look beneficial when compared with a regular soda because it replaces sugar and calories. But when a nonnutritive sweetener is compared with water or placebo, researchers can look more closely at whether the sweetener itself may have effects in the body.
One possible pathway involves the gut microbiome, the community of bacteria and other microbes that live in the digestive tract. The researchers noted that some nonnutritive sweeteners pass through the gut and come into direct contact with these microbes. In one trial included in the review, certain low-calorie sweeteners appeared to change both the composition and function of the gut microbiota.
The researchers also looked at large observational studies, which generally found that people who consume more nonnutritive sweeteners have a higher risk of cardiometabolic diseases. Those studies can be difficult to interpret, however, because people who are already at higher risk for diabetes, heart disease or weight gain may be more likely to choose diet or zero-sugar products in the first place.
The review also cautions that different sweeteners may not all work the same way. Grouping them together can make the evidence easier to analyze, but it may also hide important differences between specific ingredients.
“The rapidly increasing use of these sweeteners has outpaced our understanding of their long-term health effects,” said senior author Dariush Mozaffarian, a cardiologist and director of the Food is Medicine Institute at Tufts. “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.”
For consumers, the practical message is not that sugar-sweetened products are a better choice. Added sugar is still linked to health concerns, and reducing large amounts of it can be a meaningful step. The more useful question is whether a “zero sugar” label should automatically be treated as a sign that a product has no metabolic effect.
The researchers also pointed to a labeling gap. In the United States, manufacturers must list nonnutritive sweeteners in the ingredient list, but they do not have to say how much of each sweetener a product contains. That makes it harder for scientists to estimate intake and study long-term health effects across large groups of people.
More research is needed, especially longer and better-designed randomized trials that look at specific sweeteners, gut microbiome changes and markers of cardiometabolic health. For now, the review adds to a growing body of evidence that nonnutritive sweeteners deserve more scrutiny than their calorie counts alone suggest.
The authors reported that they did not receive support from any organization for the submitted work. Dr. Dariush Mozaffarian reported scientific advising for Branch Venture Partners, Elysium Health, Google Health, Instacart Health, January Inc., Nourish and WndrHLTH, with past advising for Brightseed, Calibrate, Filtricine, Season Health and Validation Institute. He also reported equity in HumanCo and chapter royalties from UpToDate.