This comprehensive systematic review covers a broad range of benefits and harms of NSSs in a generally healthy population of adults and children, following rigorous systematic review methods. Overall, we included 56 studies of adults and children, which assessed the associations and effects of NSSs on different health outcomes. For most outcomes, there seemed to be no statistically or clinically relevant difference between NSS intake versus no intake, or between different doses of NSSs. No evidence was seen for health benefits from NSSs and potential harms could not be excluded. The certainty of the included evidence ranged from very low to moderate, and our confidence in the reported effect estimates is accordingly limited.

Strengths and weaknesses in relation to other studies

In a preparatory mapping review,93 we identified 372 primary and secondary studies that investigated the effects of NSS intake on different health outcomes. However, the methodological and reporting quality of many publications was limited. Most studies did not contain enough information on the study design or lacked other reporting detail—that is, the sweetener used was not transparently reported, such that many the studies identified in the mapping review were not eligible for this systematic review. Studies included in this systematic review were rarely comparable with regard to their aim, design, and methods so that meaningful comparisons between them was challenging.

Although most studies reported sufficient detail for the population included, few reported sufficient information on the intervention, comparator, and outcomes. For example, comparisons of effects of different doses of sweeteners in children were not possible because most studies did not report the respective information on dose. Additionally, reported doses and outcomes measures were reported so differently that we could not assess the effect of dose on any outcome (eg, two studies8385 reported dose of aspartame and assessed eating behaviour, but the outcome was measured as energy intake or as a decrease in appetite). Furthermore, outcomes of relevance for this review were often only measured indirectly with intermediate markers. Lastly, most included studies had small sample sizes and their study duration was often too short to infer any meaningful results in the longer term.

Several other systematic and narrative reviews have examined the effects of NSSs on various health outcomes.345694959697 The methodological and clinical inclusion and exclusion criteria used in these systematic reviews differed substantially from our criteria in the present study, resulting in a different pool of included studies. The data synthesis methods also differed from the ones used in the present review. Still, the reviews found similar results to our results: Brown and colleagues4 found no strong clinical evidence for an effect of artificial sweeteners on metabolic effect in youths, whereas Cheungpasitporn and colleagues3 found no effect of artificially sweetened soda on chronic kidney disease. Greenwood and colleagues5 reported no consistent association between artificially sweetened soft drinks and diabetes risk. Onakpoya and Henegham95 reported a non-significant reduction in systolic blood pressure and significant reductions in diastolic blood pressure and fasting blood glucose with steviol glycoside compared with placebo, but indicated that the evidence was not robust due to heterogeneity.

Wiebe and colleagues6 reported a decrease in body mass index in people consuming foods and drinks containing non-caloric sweeteners compared with an increased body mass index in those consuming foods and drinks containing sucrose. The researchers further highlighted the lack of high quality research regarding non-caloric sweeteners. A systematic review by Azad and colleagues97 found no statistically significant effect of non-nutritive sweeteners on body mass index, body weight, fat mass, waist circumference, and HOMA-IR. Overall, published systematic reviews rarely drew firm conclusions. Main methodological concerns were limitations in the literature search and the data analyses. By contrast to our review, most meta-analyses were not planned and conducted, and the authors summarised the individual study results narratively instead.

A few large prospective cohort studies9899100101102 with long term follow-up investigated the association between NSS intake and different health outcomes. However, the NSSs being investigated were not sufficiently specified to match the inclusion criteria of this review. Still, their results indicate an increased risk of higher body mass index and type 2 diabetes with higher NSS consumption, or lower risk of cardiovascular disease with intake of artificially sweetened sodas compared with sugar sweetened sodas. These results partly conflict with the ones from the findings of this systematic review. Included studies investigated long term health outcomes for a relatively short duration—for example, cardiovascular health293337383944474871728586 outcomes or diabetes35373944728386 investigated for six months or less. Long term studies with sufficient statistical power are key to investigating long term health outcomes such as incidence of diabetes or cardiovascular health. Hence, results of large, long term cohort studies should be verified by studies that specify the type of sweeter used.

The findings of our review might be biased by the fact that only one reviewer assessed inclusion of studies in the initial title and abstract screening phase. Hence, relevant references could have inadvertently not been included in this review. However, this possibility is unlikely because only clearly irrelevant references were excluded at this stage. Furthermore, we did not seek clarification with the study authors about whether our assessment of risk of bias in the individual studies was correct. In the statistical analyses, missing standard deviations for change in outcomes were imputed, and in some cases, approximation was used for the analyses.103 Therefore, the reliability of analyses of changes in outcomes might have been weakened by the unavailability of data and the use of imputed values and approximation.