Association between intake of non-sugar sweeteners and health outcomes: systematic review and meta-analyses of randomised and non-randomised controlled trials and observational studies

Author(s): Toews I, Lohner S, Kullenberg de Gaudry D, Sommer H, Meerpohl JJ
Publication name: BMJ 2019; 364: k4718
Publication year: 2019


Objective: To assess the association between intake of non-sugar sweeteners (NSS) and important health outcomes in generally healthy or overweight/obese adults and children.
Design: Systematic review following standard Cochrane review methodology.
Data sources: Medline (Ovid), Embase, Cochrane CENTRAL, WHO International Clinical Trials Registry Platform,, and reference lists of relevant publications.
Eligibility criteria for selecting studies: Studies including generally healthy adults or children with or without overweight or obesity were eligible. Included study designs allowed for a direct comparison of no intake or lower intake of NSS with higher NSS intake. NSSs had to be clearly named, the dose had to be within the acceptable daily intake, and the intervention duration had to be at least seven days.
Main outcome measures: Body weight or body mass index, glycaemic control, oral health, eating behaviour, preference for sweet taste, cancer, cardiovascular disease, kidney disease, mood, behaviour, neurocognition, and adverse effects.
Results: The search resulted in 13?941 unique records. Of 56 individual studies that provided data for this review, 35 were observational studies. In adults, evidence of very low and low certainty from a limited number of small studies indicated a small beneficial effect of NSSs on body mass index (mean difference -0.6, 95% confidence interval -1.19 to -0.01; two studies, n=174) and fasting blood glucose (-0.16 mmol/L, -0.26 to -0.06; two, n=52). Lower doses of NSSs were associated with lower weight gain (-0.09 kg, -0.13 to -0.05; one, n=17 934) compared with higher doses of NSSs (very low certainty of evidence). For all other outcomes, no differences were detected between the use and non-use of NSSs, or between different doses of NSSs. No evidence of any effect of NSSs was seen on overweight or obese adults or children actively trying to lose weight (very low to moderate certainty). In children, a smaller increase in body mass index z score was observed with NSS intake compared with sugar intake (-0.15, -0.17 to -0.12; two, n=528, moderate certainty of evidence), but no significant differences were observed in body weight (-0.60 kg, -1.33 to 0.14; two, n=467, low certainty of evidence), or between different doses of NSSs (very low to moderate certainty).
Conclusions: Most health outcomes did not seem to have differences between the NSS exposed and unexposed groups. Of the few studies identified for each outcome, most had few participants, were of short duration, and their methodological and reporting quality was limited; therefore, confidence in the reported results is limited. Future studies should assess the effects of NSSs with an appropriate intervention duration. Detailed descriptions of interventions, comparators, and outcomes should be included in all reports.


The objective of the current systematic review by Toews et al. was to investigate the health effects of low/no calorie sweeteners in healthy adults and children. The study covered a wide number of outcome measures including body weight or body mass index (BMI), glycaemic control, oral health, eating behaviour, preference for sweet taste, cancer, cardiovascular disease, kidney disease, mood, behaviour, neurocognition, and adverse effects, however, it included only a limited number of studies for each outcome, excluding several high-quality randomised controlled trials (RCTs) and long-term cohort studies with repeated measurements.

The results of the review and meta-analysis showed that, among adults, findings from the few included trials comparing low/no calorie sweeteners’ intake with sugar intake suggested small improvements in BMI and fasting concentrations of blood glucose favouring low/no calorie sweeteners. Among children, intake of low/no calorie sweeteners led to a smaller increase in BMI z score than sugar intake, but there was no difference in body weight. The meta-analyses showed some beneficial impact of low/no calorie sweeteners’ use on reducing energy and sugar intake and on modest weight loss in overweight and obese individuals, i.e. the people who can benefit the most from weight loss. However, the authors conclude that there was no compelling evidence to indicate important health benefits of non-sugar sweetener use on a range of health outcomes. This conclusion is in contrast with earlier comprehensive systematic reviews and meta-analysis on low/no calorie sweeteners and body weight, supporting that, overall, the balance of evidence indicates that use of low/no calorie sweeteners in place of sugar, in children and adults, leads to reduced energy intake and body weight (Rogers et al, 2016). Much of the inconsistency among these publications stems from decisions made by Toews et al. in selecting or excluding relevant papers in the meta-analyses.

In a linked editorial in the same issue of BMJ, Vasanti Malik pointed out that: “While meta-analyses are important for guiding recommendations and policies, individual high quality studies should also be emphasised. For example, trials by de Ruyter and colleagues and Ebbeling and colleagues, the largest and most rigorously conducted so far, provide strong evidence that the replacement of sugar sweetened beverages with diet alternatives reduces weight gain in children and adolescents after one year of follow-up.” (Malik, 2019) The author concludes: “Based on existing evidence including long term cohort studies with repeated measurements and high quality trials with caloric comparators, use of NSS as a replacement for free sugars (particularly in sugar sweetened beverages) could be a helpful strategy to reduce cardiometabolic risk among heavy consumers, with the ultimate goal of switching to water or other healthy drinks.”

Several scientific experts provided comments on this study, emphasising that Toews et al. excluded several relevant RCTs in adults, and even inappropriately included one RCT which had a large effect on the overall result (Rogers, 2019). Experts noted that Toews et al. covered a unique and particularly small sub-set of existing publications (Bellisle, 2019) and that they omit or disregard many studies showing benefits from sweeteners (Winkler, 2019).

A critical appraisal of the review by Toews et al. is available on the ISA website by clicking here.

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