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KSR Number: KSRA88956

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

Risk of Bias Assessment

Overall summary: Risk of bias unclear

Bottom Line

The current evidence is limited, and does not allow to draw firm conclusions regarding the association between intake of non-sugar sweeteners and health outcomes. Results should be interpreted cautiously due to significant heterogeneity between the studies. Also, the findings of this review might be biased by the fact that only one reviewer assessed the inclusion of studies in the initial title and abstract screening phase. Hence, relevant references could have inadvertently not been included in this review. Further, well-designed high-quality studies with detailed descriptions of interventions, comparators and outcomes are needed to support these findings.

Risk of Bias Assessment

Overall summary Risk of bias unclear

Unclear

The authors acknowledged the presence of significant heterogeneity between the studies and also stated that 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.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? Probably yes
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review Unclear

Details of Review

Number of studies 56
Number of participants 203140
Last search date 23 November 2017
Review type Intervention + Aetiology
Objective To determine the association between intake of non-sugar sweeteners and important health outcomes in generally healthy or overweight/obese adults and children.
Population Generally healthy adults (≥18 years) or children (<18 years) with or without overweight or obesity.

Studies including diseased populations, pregnant women, in vitro and animal studies were excluded.
Interventions Non-sugar sweeteners (NSSs), either as an individual intervention or in combination with other NSSs.
Comparator Any alternative intervention, for example, any other type of caloric or non-caloric sweetener, any type of sugar, no intervention, placebo, or plain water.
Outcome 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.
Study design Randomised controlled trials (parallel grouped or crossover (quasi-) randomised controlled trials, and cluster randomised trials) and observational studies (prospective and retrospective cohort studies, case-control studies, and cross sectional studies).
Reference standard NA
Exposure NSSs
PP factor NR

Results

Among adults, pooled analysis of two studies reported a small beneficial effect of non-sugar sweeteners (NSSs) on body mass index (mean difference [MD] -0.6, 95% confidence interval [CI] -1.19 to -0.01, 174 participants) and fasting blood glucose (MD -0.16 mmol/L, 95% CI -0.26 to -0.06, 52 participants). However, no differences were found between the groups for outcomes body weight (MD 1.29 kg, 95% CI -2.80 to 0.21, 5 studies, 229 participants), plasma insulin levels (MD -1.60 pmol/L, 95% CI -8.39 to 5.19, 2 studies, 52 participants) and risk of cancer (odds ratio [OR] 1.03, 95% CI 0.84 to 1.25, 8 studies, 4509 participants). Also, no effect of NSSs was observed on overweight or obese adults or children actively trying to lose weight.

Four studies showed that mean daily energy intake was lower in people receiving NSSs than in those receiving sugar (1064.73 kJ, 95% Cl -1867.03 to -262.44, 4 studies, 278 participants). Lower doses of NSSs were associated with lower weight gain (-0.09 kg, 95% CI -0.13 to -0.05, one study, 17934 participants) compared with higher doses of NSSs. Three trials reported that systolic and diastolic blood pressure were lower in people receiving NSSs than in those receiving sugar or placebo (systolic, mean difference -4.90 mm Hg, 95% Cl -9.78 to -0.03; diastolic, -3.27 mm Hg, 95% CI -7.21 to 0.67, three studies, 202 participants).

Among children, a smaller increase in body mass index z score was observed with NSS intake compared with sugar intake (-0.15, 95% CI -0.17 to -0.12, two studies, 528 participants), but no significant differences were observed in body weight (-0.60 kg, 95% CI -1.33 to 0.14, two studies, 467 participants), or between different doses of NSSs.

Full Risk of Bias Assessment

The research objective was clearly stated and appropriate inclusion criteria were defined. No restrictions were reported based on study characteristics and sources of information.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Probably yes
1.2 Were the eligibility criteria appropriate for the review question? Yes
1.3 Were eligibility criteria unambiguous? Probably yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Yes
Concerns regarding specification of study eligibility criteria Low

Studies were identified by searching Medline (Ovid), Embase, Cochrane CENTRAL, WHO International Clinical Trials Registry Platform and Clinicaltrials.gov. In addition, reference lists of included studies were searched for additional findings. The search strategy was reported in full and appeared adequate. No restrictions were reported based on date, publication format, or language. One reviewer was involved in the title/abstract screening. Two reviewers were involved in full-text screening, disagreement between these two review authors was resolved by a third review author.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Probably yes
2.2 Were methods additional to database searching used to identify relevant reports? Probably yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? Probably yes
2.4 Were restrictions based on date, publication format, or language appropriate? Probably yes
2.5 Were efforts made to minimise error in selection of studies? Probably no
Concerns regarding methods used to identify and/or select studies High

Two reviewers were independently involved in the data extraction process and disagreements were resolved by discussion. Sufficient individual study characteristics have been extracted to allow interpretation of results. Relevant study results appear to have been extracted. Methodological quality assessment of included studies was assessed using the Cochrane risk-of-bias assessment tool for RCTs and the ROBINS-I tool for the assessment of non-RCT studies. Two review authors independently assessed the risk of bias for each study. Any disagreements were resolved by discussion or a third author.

3.1 Were efforts made to minimise error in data collection? Yes
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Probably yes
3.3 Were all relevant study results collected for use in the synthesis? Probably yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Yes
3.5 Were efforts made to minimise error in risk of bias assessment? Yes
Concerns regarding methods used to collect data and appraise studies Low

The synthesis appeared to have included all relevant studies. The method of analysis was explained and appeared appropriate. A number of analyses showed high heterogeneity between studies. Subgroup analyses were performed to attempt explaining the between-study heterogeneity. Publication bias could not be assessed using funnel plots due to a low number of included studies, per outcome. Sensitivity analysis was performed to check the robustness of the study results. The quality of the individual studies was considered in the synthesis.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably no
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Yes
Concerns regarding synthesis and findings Unclear

Abstract

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, Clinicaltrials.gov, 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.Systematic review registration Prospero CRD42017047668.