A critical appraisal of the systematic review by Rios-Leyvraz and Montez on health effects of low/no calorie sweeteners
Highlights
- Results of the new WHO-supported study confirm that low/no calorie sweeteners may be effective at assisting with weight loss, when used in place of sugars resulting in calorie reduction
- Evidence from controlled clinical trials supports no evidence of harm on glucose control and cardiometabolic health, contrary to results of observational studies that are prone to reverse causation and residual confounding
- Low/no calorie sweeteners are safe, including during childhood and pregnancy, as has been repeatedly and consistently confirmed by food safety authorities around the world
Three years after the publication of a systematic review by Toews and colleagues1 commissioned by the World Health Organization (WHO), aiming at studying the association between low/no calorie sweeteners’ intake and health outcomes, an updated and larger review was conducted by Rios-Leyvraz and Montez2, overcoming several of the limitations of the original study.
What did the new study find?
The results of the new WHO-supported systematic review and meta-analysis are consistent with findings of recent comprehensive systematic reviews supporting a beneficial role of low/no calorie sweeteners when used in place of sugars in the diet.3,4,5 The present meta-analyses of randomised controlled trials (RCTs), the gold standard in clinical and nutrition research, showed that the use of low/no calorie sweeteners resulted in reductions in sugars (approx. 39 g per day) and total energy intake (approx. 134 kcal), and in turn in small but significant decrease in body weight and adiposity in the short-term, especially in adults, and when used in place of sugars leading to a reduction in total calorie intake. While the authors analysed fewer studies in children, the review points to moderate certainty evidence from the study by de Ruyter et al6, a large, well-conducted RCT in which sugar-sweetened beverages were replaced with low/no calorie sweetened beverages, which found significant reductions in body weight, BMI z-score, waist circumference and body fat mass in children.
In addition, results from meta-analyses of RCTs confirmed that low/no calorie sweeteners have no adverse impact on cardiometabolic risk factors, including glucose and insulin levels, blood lipids and blood pressure. This is also in line with previously published systematic reviews and meta-analyses in healthy adults as well as in people at risk of or with diabetes.5,7,8,9
The new review also examined evidence from observational studies on a range of health outcomes. Contrary to evidence from controlled clinical trials indicating no adverse effects, results from prospective cohort studies suggested that higher intake of low/no calorie sweeteners is associated with increased risk of obesity, type 2 diabetes, cardiovascular diseases, and all-cause mortality. However, the evidence was rated as very low to low certainty, pointing to limitations of observational studies and the high possibility that the reported associations are partially or largely a result of reverse causation and/or residual confounding. The authors conclude that further research is needed to determine whether the observed associations are genuine or a result of reverse causation and/or residual confounding. In interpreting the outcomes of observational studies, it is important to consider that the collective findings from meta-analyses of RCTs do not confirm these conclusions. RCTs indicate no adverse effect of low/no calorie sweeteners’ use on intermediate cardiometabolic risk factors, and therefore, a plausible mechanism that could explain the associations reported in observational research has not been confirmed in well-conducted controlled clinical studies.
The study also reported no significant associations between low/no calorie sweeteners’ intake and several types of cancer or cancer mortality in case–control studies or meta-analysis of prospective cohort studies. However, and contrary to previous studies, this study reported a positive association between saccharin intake and bladder cancer based on meta-analyses of case–control studies, which were decades old, with important limitations and serious risk of bias. Given the low quality of the studies, the evidence was rated as very low certainty. Importantly, the safety and lack of carcinogenicity of all low/no calorie sweeteners is confirmed by food safety authorities around the world following extensive safety assessment reviews of the collective evidence from both cancer epidemiological and carcinogenicity studies, which have not been considered at all in this study.10
Finally, the study analysed observational data regarding the consumption of low/no calorie sweeteners during pregnancy concluding that further research is needed in this population group, for which prospective cohort studies suggest possible unfavourable effects of higher low/no calorie sweeteners’ consumption on risk of preterm birth and possibly adiposity in offspring later in life. However, the evidence was rated as low to very low certainty due to important limitations of these few studies. Regulatory food safety authorities worldwide, including the Joint Expert Scientific Committee on Food Additives of the United Nations Food and Agriculture Organization (FAO) and of the World Health Organization (WHO)11, the European Food Safety Authority12, and the US Food and Drug Administration13, confirm that low/no calorie sweeteners are safe, including during pregnancy and lactation. For the safety evaluation of the individual low/no calorie sweeteners, these agencies review all available data from reproductive, prenatal, and developmental toxicity studies and a breadth of tests for possible effects on mating, reproductive performance, fertility, gestational length and outcomes, skeletal and organ development, and neonatal growth and development.14
Why is this study important?
The current systematic review is an update of a previously published study by Toews et al1, commissioned by WHO, aiming to inform the forthcoming WHO draft guideline on the intake of non-sugar sweeteners for adults and children.
Following the publication of the guideline on intake of free sugars from WHO15 and global recommendations calling to reduce excess sugars intake, low/no calorie sweeteners have been used as a successful strategy to help support sugar reduction. Given their contribution to public health efforts to reduce sugars intake, WHO will consider the conclusions of this new study, together with findings of previously commissioned reviews1,8 to inform its guidance on non-sugar sweeteners’ intake.
However, while the above WHO-supported studies looked at medium- and longer-term effects of low/no calorie sweeteners on cardiometabolic health, the important short-term benefits of low/no calorie sweeteners’ use in place of sugar, for example in post-prandial blood glucose control and in dental health, should also be considered when evaluating their overall role in the diet. These benefits have also been recognised by the European Food Safety Authority (EFSA) in a scientific opinion published in 2011 stating that, “Consumption of foods containing intense sweeteners instead of sugar induces a lower blood glucose rise after their consumption compared to sugar-containing foods” and “contributes to the maintenance of tooth mineralisation”.16 Unlike sugars, low/no calorie sweeteners are not fermentable ingredients, and do not contribute to tooth decay.17,18
Considering the hierarchy of evidence in public health decisions
Contradictory results between reviews of observational studies and of RCTs have been reported before in the literature.19,20 However, experts have expressed concern about the weight that should be placed on observational data for outcomes where evidence from randomised controlled clinical studies are available.21
Inaccuracies resulting from the self-reported intake assessment methods of low/no calorie sweeteners and issues with confounding factors and reverse causality raise concerns regarding the reliability and interpretation of associations from observational studies.10,22 Observational studies, by nature, cannot prove cause and effect, and therefore, evidence from epidemiological data is rated as being of low quality and is therefore considered “weak” by the WHO.23 In all WHO-supported reviews,1,2,24 the authors stress that results of observational studies on the health effects of low/no calorie sweeteners should be interpreted with caution, and attention should focus on plausible residual confounding as well as reverse causality (“a positive association between NNS [non-nutritive sweeteners] consumption and weight gain in observational studies may be the consequence of and not the reason for overweight and obesity.”). This reinforces the importance of evidence hierarchy evaluation, particularly when considering research to inform public health decisions, which require a summary of the best-quality available evidence.
Concluding remarks
The best-quality evidence from meta-analyses of RCTs, as assessed in this review, confirms that consuming low/no calorie sweeteners leads to a significant reduction in energy intake, primarily when compared to sugars, and in turn, they may be effective at assisting with short-term weight loss, without affecting overall glucose control and other cardiometabolic risk factors. In the presence of higher-quality evidence from RCTs, low certainty evidence from observational studies should be interpreted with caution as residual confounding and reverse causality may partially or largely influence the observed associations, an issue that should be addressed in future research.
