Three years on: How the evidence on low/no calorie sweeteners has evolved since the WHO guideline

Highlights:

• The evidence base on low/no calorie sweeteners has evolved substantially since the 2023 WHO guideline, with new findings aligning across clinical trials and bias-adjusted cohort studies.
• Large, long-term clinical trials provide further evidence that low/no calorie sweeteners can aid long-term weight management.
• Bias-adjusted analyses of prospective cohorts do not support associations between low/no calorie sweeteners and increased risks of obesity, type 2 diabetes, or cardiometabolic disease, in line with findings from clinical trials.

In 2023, the World Health Organization (WHO) published a guideline on non-sugar sweeteners recommending against their use for long-term weight control and the prevention of non-communicable diseases.¹ The WHO Nutrition Guidance Expert Advisory Group (NUGAG) issued a conditional (weak) recommendation, citing uncertainty regarding long-term health benefits based on very low- to low-certainty evidence, derived primarily from observational studies. Three years later, a growing body of research has changed the evidence landscape underpinning the WHO guideline.^2-7

The balance of evidence on sweeteners has shifted since the WHO guideline

In translating evidence to recommendations, WHO NUGAG concluded that although short-term benefit of low/no calorie sweeteners use on weight management was observed in randomised controlled trials (RCTs), a lack of evidence for long-term benefits and the possibility of adverse long-term health effects based on epidemiological data offset any potential short-term benefit.¹ However, subsequent research has challenged both aspects of this conclusion.^2,3

First, regarding the perceived lack of evidence for long-term benefits in weight control, new large, long-term RCTs have reinforced the trial evidence base consistently showing that using low/no calorie sweetened food and beverages in place of sugary alternatives can help in weight management.² In these studies, individuals with overweight and obesity who incorporated low/no calorie sweetened products into their diets for up to one year achieved greater weight loss and were more successful at keeping the lost weight off, than those following diets without sweeteners.^4,5 Similar findings have also been reported in a six-month trial among people with diabetes.⁶ Importantly, no adverse cardiometabolic effects were observed with long-term sweetener use in any of these trials, supporting the conclusions by food safety authorities that approved low/no calorie sweeteners are safe when consumed within the Acceptable Daily Intake (ADI).^4-6 These findings are consistent with multiple systematic reviews and meta-analyses of RCTs showing that replacing sugars with low/no calorie sweeteners reduces energy intake, supports weight management over time, and does not affect cardiometabolic risk markers.^8-14

Second, recent research has challenged concerns regarding potential adverse long-term health effects of low/no calorie sweeteners, including increased risks of obesity, type 2 diabetes, and cardiometabolic diseases, that were derived from prospective cohort studies forming part of the WHO evidence base. A comprehensive umbrella review of meta-analyses of both RCTs and prospective cohort studies identified a substantial methodological divide between types of observational studies.³ While analyses based on single baseline dietary assessments often report associations between low/no calorie sweetener consumption and increased risks of obesity, diabetes, and cardiovascular disease, bias-adjusted analyses from prospective cohorts using repeated dietary assessments over time showed the opposite pattern and were consistent with evidence from clinical trials. Specifically, when low/no calorie sweeteners are used to replace sugar, they are associated with reductions in body weight, body fat, and energy intake in RCTs, and with lower risks of obesity, coronary heart disease, cardiovascular mortality, and all-cause mortality in bias-adjusted cohort analyses.³

These findings have been further reinforced by a recent analysis of three major prospective cohort studies with up to 32 years of follow-up conducted by Harvard University researchers, which found that increasing consumption of low/no calorie sweetened beverages was not associated with weight gain and was, in fact, linked with less weight gain over time.⁷

Aligning future public health guidance with emerging evidence

Three years after the publication of the WHO guideline, the evidence landscape has evolved considerably. The concerns that underpinned the conditional recommendation – namely a lack of evidence for long-term benefits and the possibility of adverse long-term health effects – are not supported by the most recent and methodologically robust research. Instead, current evidence indicates that replacing sugar with low/no calorie sweeteners can support long-term weight management and is associated with favourable health outcomes.^2,3

At the same time, reducing excess free sugars intake remains a global public health priority and is supported by a strong WHO recommendation.¹⁵ Identifying effective tools to help individuals achieve this goal is essential, and latest evidence reinforces that low/no calorie sweeteners can be one such tool when used as a replacement for sugar within the context of a healthy diet. As new high-quality evidence accumulates, recommendations should be reassessed to ensure they remain aligned with the best available science and support evidence-based strategies for improving public health.