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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

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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.
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RESEARCH
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
Ingrid Toews,1 Szimonetta Lohner,2 Daniela Küllenberg de Gaudry,1 Harriet Sommer,1,3
Joerg J Meerpohl1,4
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
eects.
RESULTS
The search resulted in 13941 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 benecial eect
of NSSs on body mass index (mean dierence −0.6,
95% condence 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=17934) compared with higher
doses of NSSs (very low certainty of evidence). For
all other outcomes, no dierences were detected
between the use and non-use of NSSs, or between
dierent doses of NSSs. No evidence of any eect
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 signicant dierences were observed in body
weight (−0.60 kg, −1.33 to 0.14; two, n=467, low
certainty of evidence), or between dierent doses of
NSSs (very low to moderate certainty).
CONCLUSIONS
Most health outcomes did not seem to have
dierences between the NSS exposed and unexposed
groups. Of the few studies identied for each
outcome, most had few participants, were of short
duration, and their methodological and reporting
quality was limited; therefore, condence in the
reported results is limited. Future studies should
assess the eects 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.
Introduction
Growing concerns about health and quality of life have
encouraged people to adapt healthy lifestyles and
avoid the consumption of food rich in sugars, salt, or
fat to prevent obesity and other non-communicable
diseases. With increased consumer interest in
reducing energy intake, food products containing non-
sugar sweeteners (NSSs) rather than simple sugars
(monosaccharides and disaccharides) have become
increasingly popular.1 Replacement of sugars with
NSSs bears promise of health benefits primarily by
reducing the contribution of sugars to daily calorie
intake and thus reducing the risk of unhealthy weight
WHAT IS ALREADY KNOWN ON THIS TOPIC
Studies have suggested an association between the use of non-sugar sweeteners
and health outcomes (such as body weight, diabetes, cancer, and oral health)
However, evidence for health eects due to the use of non-sugar sweeteners is
conflicting
Existing reviews on non-sugar sweeteners and health outcomes have limitations
in scope and currency
WHAT THIS STUDY ADDS
In this comprehensive systematic review, a broad range of health outcomes were
investigated to determine a possible association with non-sugar sweetener use
in a generally healthy population
There was no compelling evidence to indicate important health benets of non-
sugar sweetener use on a range of health outcomes
Potential harms from the consumption of non-sugar sweeteners could not be
excluded
1Institute for Evidence in
Medicine (for Cochrane
Germany Foundation), Medical
Centre of the University of
Freiburg, Faculty of Medicine,
University of Freiburg,
Breisacher Straße 153, 79110
Freiburg, Germany
2Cochrane Hungary, Clinical
Centre of the University of Pécs,
Medical School, University of
Pécs, Pécs, Hungary
3Institute for Medical Biometry
and Statistics, Medical Centre
of the University of Freiburg,
Faculty of Medicine, University
of Freiburg, Freiburg, Germany
4Centre of Epidemiological and
Statistical Research, Sorbonne
Paris Cité, Inserm/Université
Paris Descartes, Cochrane
France, Paris, France
Correspondence to:
J J Meerpohl
Meerpohl@cochrane.de
(ORCID 0000-0002-1333-5403)
Additional material is published
online only. To view please visit
the journal online.
Cite this as: BMJ 2019;364:k4718
http://dx.doi.org/10.1136/bmj.k4718
Accepted: 29 October 2018
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gain.2-4 However, evidence for health eects due to use
of NSSs is conflicting. While some studies report an
association between NSS use and reduced risk of type
2 diabetes, overweight, and obesity (thus suggesting
a benefit for general health and the management of
diabetes),5 6 other studies suggest that NSS use could
increase the risk of overweight, diabetes, and cancer.7
Further investigations are needed to clarify the benefits
and harms of NSS consumption. Therefore, the
objective of our review was to investigate the health
eects of NSSs in adults and children.
Description of the exposure or intervention of
interest
Most NSSs so far have been synthesised, but through
research and development in food chemistry and
processing, the number of natural NSS compounds is
increasing.8 NSSs dier from sugars not only in their
taste properties, but also in how the body metabolises
them9 and how they in turn aect physiological
processes.10 NSSs are generally sweeter than sucrose,
but contain far fewer or no calories. Each sweetener
is unique in its sweetness intensity, persistence of
the sweet taste, coating of the teeth, and aftertaste
eect.11
The definitions and terminology for NSSs vary. In
some cases, the term “artificial sweeteners” is used as
a synonym for NSSs, in other cases as a subcategory.
In this systematic review, we use the term “NSSs” as
a category including both artificial sweeteners and
naturally occurring non-caloric sweeteners (fig 1). The
term “NSSs” is also used by the CODEX Alimentarius
(part of the Joint Food and Agriculture Organisation of
the United Nations/World Health Organization Food
Standards Programme), and this review was conducted
in support of guidelines being developed by WHO.
The range of NSSs approved in dierent countries
varies. In the United States, for example, the Food
and Drug Administration has approved six NSSs
for consumption,12 whereas the range of currently
approved NSSs in the European Union is wider (eg,
including cyclamate).13 In general, current evidence
supports the safety of several NSSs to be used in
foods.14 Recognised regulatory bodies have established
acceptable daily intakes based on various safety
studies. Other NSSs are currently declared as unsafe or
have not yet been assessed.
Although many of the NSSs currently being used in
foods have been declared safe for consumption at levels
below the respective acceptable daily intakes, less is
known regarding potential benefits and harms of NSSs
within this range of intake, beacuse evidence from
studies and reviews is often limited and conflicting.
WHO is developing guidance on the use of NSSs by
adults and children based on the evidence generated
by this systematic review. Following the guidance of
the WHO Nutrition Guidance Expert Advisory Group
Subgroup on Diet and Health, this review seeks to
comprehensively assess the association between
commonly consumed NSSs and health by looking at
the following research questions:
In a general adult population, what are the eects
of NSS consumption versus no consumption on
relevant health outcomes?
In a general adult population, what are the eects
of higher versus lower NSS doses and more frequent
versus less frequent NSS consumption on relevant
health outcomes?
In an overweight or obese adult population with
explicit intentional weight loss, what are the eects
of NSS consumption versus no consumption on
relevant health outcomes?
In a general child population, what are the eects
of NSS consumption versus no consumption on
relevant outcomes?
In a general child population, what are the eects
of higher versus lower NSS doses and more frequent
versus less frequent NSSs consumption on relevant
here outcomes?
In a population of overweight and obese children
with explicit intentional weight loss, what are the
eects of NSS consumption versus no consumption
on relevant outcomes?
Methods
In accordance with the WHO guideline development
process,15 we conducted a systematic review and
meta-analyses according to the methodological
recommendations of the Cochrane Collaboration.16
Ethical approval was not required for this research.
Inclusion criteria
The inclusion and exclusion criteria for this review
were established prospectively and were based on
their relevance for a WHO global guideline for NSS
use by a generally healthy population. We included
studies with a general, healthy population of adults
(≥18 years) or children (<18 years), including those
with overweight or obesity. Studies that exclusively
included overweight or obese adults or children
who were specifically trying to lose weight (that is,
weight loss studies) were also included and analysed
separately. We excluded studies including diseased
populations, in vitro and animal studies. Studies with
pregnant women were also excluded.
The interventions and exposures of interest included
any type of NSSs, either as an individual intervention
or in combination with other NSSs. Interventions or
exposures described as “diet sodas,” “diet beverages,”
or “diet soft drinks” were included when the
sweeteners used in the products were NSSs and their
Sweeteners
Nutritive sweeteners
Sugars Modified sugars Sugar alcohols Natural caloric
sweeteners
Artificial
sweeteners
Natural
non-caloric
sweeteners
Non-sugar sweeteners
Fig1 | Types of sweeteners of interest in context
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type was suciently specified. We excluded studies
that did not specify the type of sweetener. Studies
that applied concomitant interventions were included
as long as the interventions were similar and equally
balanced between the intervention and comparator
groups to establish fair comparisons. We included
studies that reported to use NSSs within the acceptable
daily intake as established by the Joint FAO (Food
and Agriculture Organization of the United Nations)/
WHO Expert Committee on Food Additives, European
Food Safety Authority, or the United States Food and
Drug Administration (table 1), or did not report any
information on dose. If the acceptable daily intake
values diered between the regulatory bodies, we used
the higher value as the threshold for inclusion in our
review. Studies in which sweetener intake explicitly
exceeded the acceptable daily intake were excluded.
All studies had to have a minimum intervention
duration of seven days.
We included studies that compared the intervention
against the intake of any alternative intervention,
for example, any other type of caloric or non-caloric
sweetener, any type of sugar, no intervention, placebo,
or plain water. The outcomes of interest included body
weight, oral health, incidence of diabetes, eating
behaviour. Secondary outcomes were preference for
sweet taste, incidence of any type of cancer, incidence
of cardiovascular disease, incidence of chronic kidney
disease, incidence of asthma, incidence of allergies,
mood, behaviour, and neurocognition.
We included all parallel grouped or crossover
(quasi-)randomised controlled trials, and cluster
randomised trials. In crossover randomised
controlled trials, we considered both phases of
the study because the effect of NSS intake is not
expected to last long enough to bias the results
from the second phase of crossover trials for the
outcomes evaluated in this review. Furthermore,
we included non-randomised controlled trials21
as well as prospective and retrospective cohort
studies, case-control studies, and cross sectional
studies but analysed them separately. Studies with
observational design were included because the
possible long term effects of NSSs—for example,
on the incidence of non-communicable diseases
such as cancer—are generally difficult to assess
in randomised controlled trials. We included
unpublished and ongoing studies.
Search methods for identication of studies
The search strategy for this review combined
electronic searches and hand searching. For the
electronic searches, no date or language restrictions
were applied. A systematic literature search in the
following databases was conducted last on 25 May
2017 (by SL): Medline, Medline in Process and Medline
Daily Update, Embase, and the Cochrane Central
Register of Controlled Trials (CENTRAL). To identify
ongoing or completed, but unpublished trials, the
WHO International Clinical Trials Registry Platform
(ICTRP) search portal) as well as ClinicalTrials.gov
were searched on 23 November 2017 (by IT). Search
strategies are listed in the supplementary file 1. The
reference lists of relevant systematic reviews were
screened manually to identify further potentially
relevant citations.
Selection of studies
All titles and abstracts of records identified in the
databases and other sources above were screened for
eligibility by one researcher (DKdG, SL, or IT). Two
review authors independently evaluated full texts of
all potentially eligible studies for appropriateness for
inclusion without prior consideration of the results
(DKdG, SL, IT). Any disagreements were resolved by
discussion or feedback from a third author (JJM).
Data extraction and management
Two review authors independently extracted data
and cross checked the extracted information on
study characteristics, and included participants,
interventions, and reported outcomes using a piloted,
standardised data extraction form in the online software
Covidence (DKdG, SL, IT). Any dierences related to the
data extraction were resolved by rechecking the full
text of the study or by discussion. If study data were
only available from figures, data were extracted by use
of the validated software Plot Digitizer (plotdigitizer.
sourceforge.net).22 When study data were ambiguous
or data were not reported in a form that could be used
for formal comparison, we contacted the corresponding
and first author of the original publication via email.
Table1 | Amount of acceptable daily intake of non-sugar sweeteners (not exhaustive) as dened by regulatory bodies
for the general population
Non-sugar sweetener
Acceptable daily intake (mg intake per kg of body weight)
JECFAs17 European Food Safety Authority US Food and Drug Administration
Acesulfame K 15 918 15
Advantame 5 5 32.8
Aspartame 40 40 50
Brazzein Not approved Not approved
Cyclamate 11 7Not approvedNot approved
Neotame 0.3 0-219 0.30
Saccharin 15 515
Sucralose 515 5
Steviol glycosides 4 420 4
Thaumatin Not approved Not specied Not approved
JECFA=Joint Food and Agriculture Organization of the United Nations/WHO Expert Committee on Food Additives.
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Assessment of risk of bias
Two review authors independently assessed the risk of
bias for each study. Any disagreements were resolved
by discussion or a third author (JJM). For the risk of bias
assessment of randomised controlled trials, we used
the Cochrane risk of bias tool.23 For non-randomised
controlled trials, we used the ROBINS-I tool (risk of
bias in non-randomised studies of interventions).24
We planned to create funnel plots when data of 10 or
more studies were available to assess the likelihood of
dissemination bias. Since none of the meta-analyses
included 10 studies or more, a thorough assessment of
dissemination bias was not feasible.
Data synthesis
If not reported, we calculated the risk ratios and their
respective 95% confidence intervals for randomised
controlled trials, controlled clinical trials, and cohort
studies, as well as odds ratios and their respective 95%
confidence intervals for case-control studies. Mean
dierences or standardised mean dierences with 95%
confidence intervals were calculated for continuous
outcomes. We conducted meta-analyses if comparable
outcome data from two or more studies were available.
In these meta-analyses, we used the random eects
model. When baseline and final values were given,
we computed changes from baseline. We imputed any
missing standard deviation values using an imputed
correlation coecient.25 In this review, we used a
correlation coecient of zero. Statistical analyses
were conducted by the statistical software R with the R
package meta and metasens.26
Sensitivity analyses
We tested the robustness of our results using
sensitivity analyses. In forest plots, we reported
results of analyses with the random eects model as
our primary eect estimate. For all meta-analyses, we
conducted sensitivity analyses using the fixed eect
model. In most sensitivity analyses with the fixed eect
model, the eects were more precise (narrower 95%
confidence intervals) and consequently statistically
significant at times, compared with analyses using
the random eects model. However, given the clinical
heterogeneity of the included studies, these were
judged to not be appropriate, and therefore the results
are not reported in detail. We found only one study with
low risk of bias; thus, an analysis of studies with a low
risk of bias only was not feasible. Study populations
were divided into participants aged 18 years and older
and those aged younger than 18 years in sensitivity
analyses so that the eect of NSSs on children only and
adults only could be analysed.
Assessment of the certainty of the evidence
We used the GRADE approach (grading of
recommendations assessment, development, and
evaluation) to assess the certainty of the evidence for
the most relevant, available measures of all critical
and important outcomes.27 According to the GRADE
approach, we classified the certainty of evidence in four
categories: high, moderate, low, and very low certainty
of evidence. The GRADE certainty assessment per
outcome was documented in GRADE evidence profiles,
together with the pooled eects for the interventions.
We used GRADEpro GDT online software28 to compile
the evidence profiles. Assessments of the certainty of
evidence for all outcomes were reviewed with the WHO
Nutrition Guidance Expert Advisory Group Subgroup
on Diet and Health as part of the WHO guideline
development process.
For the outcomes with available evidence from
randomised controlled trials, additional evidence
from non-randomised studies and observational
studies can be found in the supplementary materials
(supplementary file 1, table 1). If case-control studies
and cross sectional studies provided the best available
body of evidence, we presented this evidence in the
main text. Presentation of the results in this systematic
review is primarily structured according to age group
(adults or children) and outcome. Within the each
outcome, we presented the results for each PICO
question separately (that is, population, intervention,
comparator, and outcome), describing results of
randomised controlled trials first, followed by those of
non-randomised and observational studies.
Patient and public involvement
No patients were involved in setting the research
question or the outcome measures, nor were
they involved in developing plans for design or
implementation of this systematic review. No patients
were asked to advise on interpretation or writing up of
results. The results of this review will be disseminated
to appropriate audiences. It was not evaluated whether
the studies included in the review had any patient
involvement.
Results
Details of the study selection are presented in figure 2.
Key characteristics of all included studies are available
in supplementary file 3.
Detailed results of the assessment of risk of bias
in included randomised controlled trials (n=21) are
summarised in supplementary file 1. Unclear reporting
about random sequence generation and allocation
concealment were the main reasons for unclear risk
of bias in randomised controlled trials, while lack
of blinding of participants and personnel was the
main reason for high risk of bias. Other potential
sources of bias were rarely suspected. The overall risk
of bias assessment of controlled clinical trials and
observational studies (n=35) was serious mainly due
to suspected bias caused by confounding, and bias
caused by classification of the intervention. The risk
of bias assessment for individual non-randomised
studies can be found in supplementary file 2.
NSS intake and health outcomes in adults
We included 17 randomised controlled trials,18 29 30-44
six controlled clinical trials,45-49 five prospective or
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retrospective cohort studies,50-54 15 case-control
studies,55-69 and five cross sectional studies70-74 in
our assessment of the association between health
outcomes and NSS intake in adults. We identified seven
ongoing studies in adults75-81 and one study awaiting
classification.82
Body weight
In randomised controlled trials, we saw no significant
dierences in change in body weight between adults
receiving NSSs compared with those receiving dierent
sugars or placebo (mean dierence 1.29 kg, 95%
confidence interval −2.80 to 0.21; five studies, n=229,
very low certainty of evidence; fig 3). Only one study
used placebo as a comparator38 while the other studies
used caloric sweeteners as a comparator.34 37 39 40
There seemed to be no consistent dierence in eect
between studies using aspartame,34 37 40 stevia,38 or a
combination of sweeteners39 as the intervention.
Subgroup analysis by body weight status suggested
that NSS use by overweight or obese individuals (that
is, those not trying to lose weight, mean body weight
86.87 kg) resulted in reduced body weight of 1.99
kg (95% confidence interval −2.84 to −1.14; three
studies, n=146, duration of studies, four weeks to six
months) but no change in individuals of normal weight
(0.03 kg, −0.03 to 0.09; two, n=110; fig 3). As assessed
in randomised controlled trials, change in body mass
index was 0.6 units lower in adults receiving NSSs than
in those receiving sucrose (95% confidence interval
−1.19 to −0.01; two studies, n=174, low certainty of
evidence). Otherwise, randomised controlled trials,
non-randomised controlled trials, and observational
studies comparing NSS use with no use and with
insucient data for a meta-analysis indicated no
consistent dierence between the intervention and
control group in relation to dierence in body weight
and other measures of overweight and obesity
(supplementary material file 1, table 1).
In one cohort study,50 researchers assessed dierent
levels of NSS intake and reported that weight gain
was 0.09 kg lower in women consuming up to 5.8 g
saccharin per day compared with women consuming
more than 5.8 g saccharin per day (95% confidence
interval −0.13 to −0.05; one study, outcome assessed
in n=17934, very low certainty of evidence). Two
randomised controlled trials31 32 investigated the eect
of NSS intake in overweight populations trying to lose
weight, although they did not provide enough data
to conduct meta-analysis (standard error or standard
deviation not reported). One study31 showed no
dierence in body weight between the study groups
(mean dierence 0.10 kg, 95% confidence interval
−0.31 to 0.11; n=163, low certainty of evidence).
The other study32 showed no significant dierences
between the study groups with regard to reduction in
body weight, body mass index, or body fat.
Diabetes or glycaemic control
In two randomised controlled trials, levels of fasting
blood glucose were 0.16 mmol/L lower in the groups
receiving aspartame or a combination of NSSs than
in groups receiving sugar (95% confidence interval
−0.26 to −0.06; two studies, n=52, very low certainty
of evidence).37 39 However, no dierences were
observed in plasma insulin levels (mean dierence
−1.60 pmol/L, 95% confidence interval −8.39 to 5.19;
two, n=52) or in insulin resistance and β cell function
as measured by the homoeostatic model assessment
of insulin resistance (HOMA-IR; −0.14, −0.38 to
0.10; two, n=66, very low certainty of evidence).37 39
Additional markers for diabetes were reported by single
studies only (supplementary material file 1, table 2).
Eating behaviour
Energy intake and appetite—Pooled data from four
randomised controlled trials18 39-41 (n=318 at baseline)
showed that mean daily energy intake was 1064.73 kJ
lower in people receiving NSSs than in those receiving
sugar (95% confidence interval −1867.03 to −262.44;
four studies, n=278, very low certainty of evidence;
fig 4). Subgroup analysis by study duration and type
of sweetener used as the intervention indicated that
this result was largely being driven by one study
that lasted for 10 weeks and used a combination of
aspartame, cyclamate, acesulfame K, and saccharin
(mean dierence −2597.00, 95% confidence interval
−3125.35 to −2068.65; n=42). Studies of short
duration (lasting four weeks) using aspartame as
the intervention did not show a significant reduction
(−598.94, 95% confidence interval −1445.24 to
247.36; three studies, n=276). In one randomised
Additional records identified through
other sources aer duplicates removed
Full text articles excluded
Wrong publication format
Study duration too short
Sweetener not defined
Wrong study type
Not a primary human study
Wrong intervention
Wrong study population
No relevant health outcome described
No direct or concurrent comparison
Duplicate
Full text not available
Reason not recorded
257
125
117
101
82
74
42
30
20
17
14
16
Records screened
911
Records identified through
database searching aer duplicates removed
895
13 030
Records excluded
12 970
13 941
Full text articles assessed for eligibility
971
Studies included in qualitative synthesis
57
Studies included in quantitative synthesis (meta-analysis)
56
Fig2 | Risk of bias in included randomised controlled trials with data for analyses
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controlled trial,38 researchers reported narratively
(that is, without numerical data) that there were
no significant dierences in energy intake between
the stevia and placebo groups. Data from two non-
randomised controlled trials45 46 (n=22) suggested no
dierence between the intervention and control groups
for energy intake.
One randomised controlled trial29 investigated
the eect of NSSs on energy intake in overweight
populations trying to lose weight. In this study, mean
daily energy intake was reported to be 548 kJ lower in
the group receiving NSSs than in the group avoiding
NSSs (95% confidence interval −692.73 to −403.27;
n=128). In addition, no significant dierences were
observed for self control with respect to eating (mean
dierence −0.20, 95% confidence interval −1.03 to
0.63; n=186, low certainty of evidence) or feelings of
hunger (−0.20, −1.03 to 0.63; n=186, low certainty of
evidence). In another randomised controlled trial,30
researchers reported narratively that self reported
appetite remained the same in groups receiving NSSs
as well as those receiving no intervention over the
study period of 12 weeks.
Sugar intake and sweet preferenceThe pooled
eect from three randomised controlled trials18 39 40
showed that daily sugar intake was 89.71 g lower in
adults receiving NSSs than in those receiving sugar
(95% confidence interval −127.63 to −51.80; three
studies, n=135, very low certainty of evidence; fig 5).
All three studies included overweight or obese
participants. Both studies by Reid18 40 measured
sugar intake by including the sucrose from the control
intervention in their outcome measure. Data from two
non-randomised controlled trials46 49 and one cross
sectional study72 showed no dierences in sugar intake
between the intervention and control groups.
Two randomised controlled trials31 32 investigated
the eect of NSSs on preference for sweet taste or sugar
intake in overweight populations trying to lose weight.
The preference for sweet taste, as assessed by desire for
sweets (measured on a 0-10 scale with higher values
indicating increased desire), was slightly lower in the
group receiving NSSs than in the group not receiving
NSSs (mean dierence −0.2, 95% confidence interval
−0.34 to −0.06; one study, n=186, moderate certainty
of evidence). Sugar intake was similar between the
groups after three years of follow-up (−0.00 g, −0.18 to
0.18; one, n=186).31
Cancer
The risk for bladder or lower urinary tract cancer
as assessed in meta-analysis of case control studies
seemed to be similar in those exposed to sweeteners
and those unexposed to sweeteners (odds ratio 1.03,
95% confidence interval 0.84 to 1.25; eight studies,
n=4509, very low certainty of evidence; fig 6). The
odds ratios for other types of cancer as reported in
various observational studies suggested no dierence
in risk for dierent cancers except for ovarian cancer
(0.61, 0.38 to 0.98; one case-control study, n=459)
and pancreatic cancer (0.19, 0.08 to 0.46, one case-
control study, n=978). The certainty of evidence for the
risk of dierent types of cancers was very low.
We saw no association between consumption
of higher doses of aspartame and incidence of the
main subtypes of lymphoid cancers, non-Hodgkin
lymphoma subtypes (P=0.69), or non-lymphoid
leukaemia, in two prospective cohort studies with up
to 10 years of follow-up (n=473984).52 53 Similarly, no
association was seen between consumption of higher
NSS doses and lower urinary tract cancer (n=149, very
low certainty of evidence) in one case-control study.66
Blood pressure
Data from three randomised controlled trials showed
that systolic and diastolic blood pressure were lower
in people receiving NSSs than in those receiving sugar
or placebo (systolic, mean dierence −4.90 mm Hg,
95% confidence interval −9.78 to −0.03; diastolic,
−3.27 mm Hg, −7.21 to 0.67; three studies, n=202 at
baseline, very low certainty of evidence).37-39 The eect
seemed stronger in studies using caloric sweeteners as
comparators37 39 than in those that used a non-caloric
comparator.38 In another randomised controlled trial,
researchers reported narratively that there was no
change in blood pressure in the study groups.29
No significant dierences in systolic and diastolic
blood pressure were reported in one randomised
controlled trial assessing the eect of aspartame in
overweight populations trying to lose weight.32 After
12 weeks, the group dierences in diastolic blood
pressure were 6 mm Hg less in men and 1 mm Hg more
in women when the aspartame group was compared
with controls (not enough data for formal statistical
comparison, very low certainty of evidence).
Other outcomes
In studies comparing NSS intake with no intake, we
found an increased risk of depression in one cohort study
(odds ratio 1.14, 95% confidence interval 1.02 to 1.27;
n=263923).51 We also found no eects on the incidence
of kidney disease (very low certainty of evidence),44
mood (moderate certainty of evidence),18 29 40 42
behaviour (very low certainty of evidence),83
neurocognition (low certainty of evidence),42 or risk of
Normal weight
Kuzma 2015
Maki 2008
Pooled estimate
Heterogeneity: τ2=0, P=0.67, I2=0%
Overweight and obese
Maersk 2012
Reid 2014
Raben 2001
Pooled estimate
Heterogeneity: τ2=0.51, P<0.01, I2=93%
Overall effect: τ2=2.75, P<0.01, I2=99%
-0.43 (-2.53 to 1.66)
0.03 (-0.03 to 0.09)
0.03 (-0.03 to 0.09)
-1.00 (-1.66 to -0.32)
-2.02 (-2.35 to -1.69)
-2.80 (-3.11 to -2.49)
-1.99 (-2.84 to -1.14)
-1.29 (-2.80 to 0.21)
-3 -2 -1 1 203
Study Mean difference
(95% CI)
Mean difference
(95% CI)
15.2
21.5
36.7
20.6
21.3
21.3
63.3
100.0
Weight
(%)
Fig3 | Eect of non-sugar sweetener intake on weight change (kg) in adults
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adverse events (eg, skin reactions, loss of appetite, and
headaches; risk ratio 0.65, 95% confidence interval
0.16 to 2.59; three studies, n=167, low certainty of
evidence).29 42 44 We identified no studies investigating
the incidence of asthma or the incidence of allergies.
In studies comparing dierent doses of NSS intake,
evidence from one crossover randomised controlled
trial36 indicated a significant increase in depression
in people consuming the higher aspartame dose
compared with those consuming the lower dose (low
certainty of evidence). The study reported significantly
better results in participants receiving lower doses
of aspartame with respect to neurocognition (low
certainty of evidence), but no dierence in adverse
events for higher intake versus lower intake of
aspartame (low certainty of evidence).36 Similarly, in
two randomised controlled trials,31 32 no significant
dierences in the risk for adverse events were observed
between individuals receiving NSSs and those not
receiving NSSs in overweight populations trying to lose
weight (risk ratio 1.38, 95% confidence interval 0.58
to 3.28; n=204, low certainty of evidence). Detailed
results on all outcomes are reported in supplementary
file 1.
NSS intake and health outcomes in children
Overall, we identified four randomised controlled
trials,84-87 two non-randomised controlled trials,83 88
one case-control study,89 and one cross sectional
study70 that contributed data to our review regarding
the association between NSS intake and health
outcomes in children. We identified one ongoing study
in children.90
Body weight
Two randomised controlled trials85 91 found a similar
weight gain in children receiving sucralose and
acesulfame K91 or aspartame85 and children receiving
sucrose (mean dierence −0.60 kg, 95% confidence
interval −1.33 to 0.14; two studies, n=467, low
certainty of evidence; fig 7). After exclusion of the
oldest age group (13-21 years) from one study85 in
a sensitivity analysis, we saw no dierence in eect
(−0.50 kg, −1.43 to 0.42; two, n=722). Two randomised
controlled trials87 92 reported a significantly smaller
increase in body mass index z score in children
receiving sucralose and acesulfame K91 or sucralose
alone,87 compared with children receiving sucrose
(−0.15, −0.17 to −0.12; n=528, moderate certainty of
evidence).
One randomised controlled trial92 (n=641)
reported no group dierences in body fat measured
by electrical impedance (mean dierence −0.83%
body fat, 95% confidence interval −2.12% to 0.46%),
waist circumference (−0.50 cm, −1.73 to 0.73),
skinfold thickness (−1.5 mm, −4.71 to 1.71), and
waist-to-height ratio (−0.50%, −1.73 to 0.73). In one
randomised controlled trial including overweight or
obese children involved in a weight loss programme,86
researchers reported a lower weight gain in children
receiving aspartame than in children receiving placebo
(−0.75 kg, −1.08 to −0.43; one study, n=57, low
certainty of evidence).
Dental health
In one non-randomised controlled trial,88 mouth rinses
with chlorhexidine were more eective than stevioside
in decreasing plaque volume. Plaque volume was
similar in the groups using water or stevioside (low
certainty of evidence).
Eating behaviour
Satiety, appetite, and energy intake—In one randomised
controlled trial (n=141), children receiving NSSs
versus those receiving sucrose had similar self reported
satiety one minute after intake (odds ratio 0.77, 95%
confidence interval 0.46 to 1.29) and 15 minutes after
intake (1.44, 0.86 to 2.40).84 Self reported appetite
increase (risk ratio 0.84, 95% confidence interval
0.22 to 3.29) or appetite decrease (1.08, 0.44 to 2.63)
were similar between the study groups in another
randomised controlled trial (n=126).85 According to
evidence from a third randomised controlled trial,
energy intake was lower in the sucralose group than
in the sucrose group (mean dierence 197.60 kJ,
95% confidence interval −327.18 to 722.38; n=190,
low certainty of evidence).87 In one non-randomised
controlled trial, mean daily energy intake was reported
to be similar between the groups receiving aspartame
or saccharin and significantly increased in the group
that received sucrose.83 Energy intake was 6711, 6640,
or 7728 kJ daily with aspartame, saccharin, or sucrose
in the preschool group, respectively, and 8100, 8284,
and 9293 kJ for school age children, respectively.
In one randomised controlled trial with overweight
children involved in active weight loss, researchers
assessed change in appetite as self reported adverse
events, which were reported to be no dierent between
the study groups (incidence rate ratio 0.94, 95%
confidence interval 0.35 to 2.49; one study, n=55, very
low certainty of evidence).86
Preference for sweet taste—One crossover non-
randomised controlled trial83 (n=47) reported
significantly lower sugar intake in children receiving
aspartame or saccharin than in children receiving
sucrose (not enough data for formal statistical
comparison, very low certainty of evidence). The eect
seemed to be strongly related to the sugar content of
the experimental diets.
Diabetes
In one crossover non-randomised controlled trial,83
researchers found a significantly higher increase in
blood glucose in children of preschool age receiving
aspartame compared with sucrose (mean dierence
0.24 mmol/L, 95% confidence interval 0.09 to 0.39;
n=25), a significantly higher increase in blood glucose
in children of school age receiving saccharin compared
with sucrose (0.65 mmol/L, 0.44 to 0.86; n=23), and a
significantly lower increase in blood glucose in children
of preschool age receiving aspartame compared with
saccharin (−0.75 mmol/L, −0.95 to −0.64; n=23, very
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low certainty of evidence). In overweight children
involved in active weight loss, blood glucose decreased
less strongly in those receiving NSSs compared with
those not receiving NSSs (0.3 mmol/L, 0.2 to 0.4;
n=49, very low certainty of evidence).86
Cancer
In one case-control study89 (n=150), researchers
reported no dierence in risk for primary brain
tumours when looking at aspartame intake from all
sources (risk ratio 1.1, 95% confidence interval 0.5 to
2.6) or aspartame intake from diet drinks only (0.9, 0.3
to 2.4; very low certainty of evidence). Furthermore,
no dierence in risk of primary brain tumours was
seen with dierent durations or frequencies of
aspartame intake (very low certainty of evidence; see
supplementary material file 1, table 4).
Cardiovascular disease
In one randomised controlled trial,85 total cholesterol
concentration decreased strongly in sucrose groups
but increased in the aspartame group (mean dierence
0.44 mmol/L, 95% confidence interval 0.33 to 0.56;
n=45). The change in triglyceride concentration (4.00,
−0.50 to 8.50; n=45, unit of measurement not reported)
and blood pressure (no numerical data reported, very
low certainty of evidence) were similar between the
study groups. Another randomised controlled trial86
reported that in overweight children involved in active
weight loss, systolic and diastolic blood pressure were
similar in those receiving NSSs or placebo (systolic,
mean dierence 1.00 mm Hg, 95% confidence interval
−0.95 to 2.95; diastolic, 1.00 mm Hg, −0.53 to 2.53;
n=55, very low certainty of evidence).
Kidney disease
In randomised controlled trials, no dierences
were observed in concentrations of creatinine (an
intermediate marker for kidney disease) between
NSS intake and no intake in overweight children
involved in weight loss studies (mean dierence 0.002
mmol/L, 95% confidence interval −0.001 to 0.005;
one, n=49, very low certainty of evidence).86 Similarly,
no corresponding dierence was seen in children of
healthy weight (0.003, −0.012 to 0.018; one, n=126 at
baseline, very low certainty of evidence).85 86 However,
after exclusion of the oldest age group (13-21 years)
in a sensitivity analysis, creatinine decreased more
strongly in the sucrose group (0.011, 0.004 to 0.018;
n=80).
Other outcomes
In one non-randomised controlled trial, we found no
dierence in eect between children receiving NSSs
and those not receiving NSSs on self rated mood
states (very low certainty of evidence),83 behaviour
(very low certainty of evidence),83 and cognitive
performance (low certainty of evidence).83 One
randomised controlled trial87 described significantly
worse neurocognitional performance in tests of
cognitive abilities in children receiving NSSs than
in children receiving sugar (n=386). Another
randomised controlled trial reported no dierence in
the occurrence of adverse events between children
receiving NSSs and children not receiving NSSs (risk
ratio 1.28, 95% confidence interval 0.86 to 1.91;
n=126, low certainty of evidence).85 However, in one
randomised controlled trial, a higher risk of adverse
eects in overweight children involved in active
weight loss not receiving NSSs versus those receiving
NSSs was observed (incidence rate ratio 1.37, 95%
confidence interval 1.05 to 1.79; n=55, low certainty
of evidence).86 Overall, 103 adverse eects were noted
in the intervention group and 113 in the control group.
We identified no studies investigating the eect of NSS
intake on incidence of asthma or allergies.
Discussion
Principal ndings
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 eects of NSSs on
dierent health outcomes. For most outcomes, there
seemed to be no statistically or clinically relevant
dierence between NSS intake versus no intake, or
between dierent doses of NSSs. No evidence was
seen for health benefits from NSSs and potential
harms could not be excluded. The certainty of the
Short duration
Reid 2007
Reid 2010
Reid 2014
Pooled estimate
Heterogeneity: τ2=5.5e+05, P<0.01, I2=99%
Long duration
Raben 2001
Pooled estimate
Heterogeneity: not applicable
Overall effect: τ2=6.5e+05, P<0.01, I2=99%
-1185.57 (-1295.75 to -1075.39)
-530.00 (-842.94 to -217.06)
-81.50 (-94.38 to -68.62)
-598.94 (-1445.24 to 247.36)
-2597.00 (-3125.35 to -2068.65)
-2597.00 (-3125.35 to -2068.65)
-1064.73 (-1867.03 to -262.44)
-3000 -1500 15000 3000
Study Mean difference
(95% CI)
Mean difference
(95% CI)
25.8
24.9
25.9
76.7
23.3
23.3
100.0
Weight
(%)
Fig4 | Eect of non-sugar sweetener intake on daily energy intake (kJ) by study duration
(4 or 10 weeks)
Reid 2001
Reid 2010
Reid 2014
Pooled estimate
Heterogeneity: τ2=1103,
P<0.01, I2=98.4%
-126.00 (-133.24 to -118.76)
-59.62 (-70.18 to -49.06)
-83.10 (-90.96 to -75.24)
-89.71 (-127.63 to 51.80)
-150 -100 -50 500
Study Mean difference
(95% CI)
Mean difference
(95% CI)
33.5
33.1
33.4
100.0
Weight
(%)
Fig5 | Eect of non-sugar sweetener intake on daily sugar intake (g) in adults
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included evidence ranged from very low to moderate,
and our confidence in the reported eect 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
eects of NSS intake on dierent 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 sucient detail
for the population included, few reported sucient
information on the intervention, comparator, and
outcomes. For example, comparisons of eects of
dierent 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
dierently that we could not assess the eect of dose
on any outcome (eg, two studies83 85 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 eects of NSSs on various health
outcomes.34 56 94-97 The methodological and clinical
inclusion and exclusion criteria used in these
systematic reviews diered substantially from our
criteria in the present study, resulting in a dierent pool
of included studies. The data synthesis methods also
diered 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 eect of artificial sweeteners on metabolic eect
in youths, whereas Cheungpasitporn and colleagues3
found no eect 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
eect 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 studies98-102 with long
term follow-up investigated the association between
NSS intake and dierent health outcomes. However,
the NSSs being investigated were not suciently
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 health29 33 37-39 44 47 48 71 72 85 86
outcomes or diabetes35 37 39 44 72 83 86 investigated for
six months or less. Long term studies with sucient
statistical power are key to investigating long term
health outcomes such as incidence of diabetes or
de Ruyter 2012
Frey 1976
Pooled estimate
Heterogeneity: τ2=0.204, P=0.06, I2=72%
-0.97 (-1.52 to -0.42)
-0.22 (-0.78 to 0.35)
-0.60 (-1.33 to 0.14)
-0.5 0 1.5-1.0 1.00.5-1.5
Study Mean difference
(95% CI)
Mean difference
(95% CI)
50.4
49.6
100.0
Weight
(%)
Fig7 | Eect of non-sugar sweetener intake on risk (odds ratio) of bladder cancer. Odds
ratio of less than 1=increased risk of cancer with non-sugar sweeteners
Simon 1975
Kessler 1978
Cartwright 1981
Najem 1982
Möller-Jensen (Saccharin) 1983
Möller-Jensen (Cyclamate) 1983
Mommsen 1983
Nomura 1991
Momas 1994
Pooled estimate
Heterogeneity: τ2=0.027, P=0.16, I2=32%
1.00 (0.59 to 1.70)
0.88 (0.62 to 1.25)
1.20 (0.93 to 1.55)
1.25 (0.57 to 2.75)
0.76 (0.53 to 1.07)
0.84 (0.34 to 2.07)
6.73 (1.30 to 34.78)
0.96 (0.64 to 1.46)
1.50 (0.75 to 3.00)
1.03 (0.84 to 1.25)
0.1 0.5 1 102
Study Odds ratio
(95% CI)
Odds ratio
(95% CI)
10.2
17.3
23.1
5.4
17.3
4.3
1.4
14.3
6.7
100.0
Weight
(%)
Fig6 | Eect of non-sugar sweetener intake on risk (odds ratio) of bladder cancer. Odds
ratio of less than 1=increased risk of cancer with non-sugar sweeteners
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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.
Implications for clinicians and policy makers,
unanswered questions, and future research
This review was prepared to inform a WHO guideline
on NSS use. The guideline will provide information on
implications for actions by health experts and policy
makers. So far, several studies on the eects of NSSs
on dierent health outcomes have been conducted.
However, their methodological or reporting quality
is mostly limited and often not suciently detailed
to include their results in meta-analyses. Moreover,
included studies diered substantially in their
design (that is, choice of population, intervention,
comparator, and outcome measures). Given these
relevant dierences between studies, a reliable review
of the eects by type of sweetener or of the caloric
eects versus non-caloric eects is challenging. Type
of intervention and comparator might aect health
outcomes dierently and should be considered in
future research.
We also recommend that future studies assess
the eects of NSS use on health outcomes with an
appropriate study duration. Study planning should
consider the duration necessary for plausible,
relevant eects to occur in the dierent outcomes of
interest. Longer term studies are needed to assess
eects on overweight and obesity, risk for diabetes,
cardiovascular disease, and kidney disease. Type and
dose of sweetener use should be reported precisely
and transparently in all studies. Precise reporting
of sweetener content (that is, type and amount of
sweeteners) in ready-to-consume foods and beverages
is highly desirable and could be helped by more
detailed information on ingredients as provided
by manufacturers. Consistent use of core outcome
measures and consensus on timing and mode of
assessment would further help researchers pool data
across studies. In addition to studying the eects on
NSS use in a general healthy population of adults
and children, research should focus on diseased
populations and other subgroups, including pregnant
women and their ospring and people who use NSSs
in amounts higher than average (such as those with
diabetes).104
Most of the studies identified for this review used
single sweeteners and the use patterns of sweeteners
in the studies might dier from that in real life
practice.105 Therefore, the certainty in the evidence
presented in this review might further be aected by
indirectness. For example, NSSs can be consumed
in dierent ways, including as a table top sweetener
(that is, added to tea or coee as a replacement
for sugar) where the dose is freely determined by
users themselves and might be higher than in that
recorded the studies. Moreover, by contrast to many
of our included studies that used a single NSS only,
many food items have dierent types of NSSs that
are combined to cover dierent bitter or metallic
aftertastes of individual sweeteners and provide an
adequate sweetness. Future research might consider
exploring the eects of dierent combinations of
sweeteners in doses similar to real life use patterns
and compare the eects of higher versus lower NSS
doses. Development and research on NSSs is ongoing,
and new alternatives to sugar are presented on a
regular basis. Therefore, we also need data on the
safety and benefits and harms of other sweeteners not
assessed in this review for a comprehensive overview
of the health eects of NSSs.
Results of observational studies on the health
eects of NSSs should be interpreted with caution,
and attention should focus on plausible residual
confounding as well as reverse causality (such as a
higher consumption of NSSs by overweight or obese
populations aiming at weight management).106
Appropriate long term studies that consider baseline
consumption of sugar and NSSs105 and have an
appropriate comparator106 should investigate whether
NSSs are a safe and eective alternative to sugar, and
results should be interpreted in light of these study
design characteristics.105 106
The WHO Nutrition Guidance Advisory Group (NUGAG) Subgroup on
Diet and Health provided valuable insight on aims and objectives of
this review. WHO agreed to the publication of this systematic review
in a scientic journal because it serves as the background evidence
review for WHO guidelines on non-sugar sweeteners and should
therefore be available widely.
Contributors: SL, IT, and JJM conceived and designed the review. JJM
coordinated the review. SL, JJM, and IT designed the search strategy.
SL and IT undertook the searches and screened the search results. IT
organised the retrieval of the papers. SL, IT, DKdG, and JJM screened
the papers against eligibility criteria. SL, IT, and DKdG appraised
the quality of the papers. SL, IT, DKdG, and HS extracted data from
the papers. HS analysed the data. SL, JJM, IT, and DKdG interpreted
data. IT, SL, DKdG, and JJM wrote the review and its protocol. JJM,
SL, and DKdG provided general advice on the review. JJM secured
funding for the review. SL, JJM, and IT performed previous work that
was the foundation of the current review. JJM is the guarantor of
this manuscript. The questions guiding the review were discussed
and developed by the WHO NUGAG Subgroup on Diet and Health,
and the study protocol was approved, by the NUGAG Subgroup
on Diet and Health. Neither WHO nor the WHO NUGAG Subgroup
on Diet and Health played a role in data collection or analysis. All
authors, external and internal, had full access to all of the data
(including statistical reports and tables) in the study and can take
responsibility for the integrity of the data and the accuracy of the
data analysis. The corresponding author attests that all listed
authors meet authorship criteria and that no others meeting the
criteria have been omitted.
on 3 January 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.k4718 on 2 January 2019. Downloaded from
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thebmj
BMJ
2019;364:k4718 | doi: 10.1136/bmj.k4718 11
Funding: The research was funded by WHO. The research was
conducted independently from the funder, and researchers are
independent from the funder.
Competing interests: All authors have completed the ICMJE uniform
disclosure form at www.icmje.org/coi_disclosure.pdf and declare:
support from WHO for the submitted work; no nancial relationships
with any organisations that might have an interest in the submitted
work in the previous three years; no other relationships or activities
that could appear to have influenced the submitted work.
Ethical approval: Ethical approval was not required for this research.
Data sharing: Full datasets can be obtained from the corresponding
author at Meerpohl@cochrane.de.
The lead author arms that the manuscript is an honest, accurate,
and transparent account of the study being reported; that no
important aspects of the study have been omitted; and that any
discrepancies from the study as planned (and, if relevant, registered)
have been explained.
This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this work
non-commercially, and license their derivative works on dierent
terms, provided the original work is properly cited and the use is non-
commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Supplementary file 1: Supplementary materials
Supplementary file 2: Results of the assessment of
risk of bias in included observational studies
Supplementary file 3: Details of included
studies (RCT=randomised, controlled trial; non-
RCT=non-randomised controlled trial; AS=artificial
sweetener, CVD=cardiovascular disease); *For profit
funding includes sponsoring of study material,
i.e. intervention substances, as well as financial
sponsoring for conducting the study
on 3 January 2019 by guest. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.k4718 on 2 January 2019. Downloaded from
... To inform the development of WHO guidance on NSS intake, a systematic review was commissioned and published in 2019 (1). The current review is an update and expansion of that review: it updates the review with new studies published since the search was conducted in the original review, and also includes studies excluded from the original review in which NSS were not specified by name, as well studies assessing the effects of NSS intake in pregnant women. ...
... We conducted a multipronged search, building on the search conducted in the original systematic review (1). This included: ¢ ¢ screening the excluded studies list from the original review for studies that were excluded because the NSS was unspecified; ...
... ¢ ¢ systematically searching MEDLINE, 1 Embase and the Cochrane Central Register of Controlled Trials (CENTRAL), from 1 January 2017 to 26 July 2021 to update the original review; and ¢ ¢ because we slightly modified the search strategy used in the original review to increase the sensitivity, searching the same databases with the added or modified terms and without date restrictions to pick up any relevant studies not included in the original search. ...
Technical Report
Non-sugar sweeteners have been developed as an alternative to sugars and are widely used both as an ingredient in pre-packaged foods and beverages and added to food and beverages directly by the consumer. Individual non-sugar sweeteners undergo toxicological assessment by the by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and other authoritative bodies to establish safe levels of intake (i.e. acceptable daily intake or ADI). While results of randomized controlled trials have generally suggested non-sugar sweeteners may have little impact on glucose metabolism and result in lower body weight when coupled with energy restriction in the short-term, there is no clear consensus on whether non-sugar sweeteners are effective for long-term weight loss or maintenance, or if they are linked to other long-term health effects at intakes within the ADI. This systematic review brings together the most current scientific evidence on health effects of non-sugar sweetener use. https://www.who.int/publications/i/item/9789240046429
... ex. aspartame, saccharine, glycosides de stéviol), ne sont pas considérées comme des alternatives plus saines 17 , en raison d'un manque d'évidences claires sur leurs effets à long terme sur la santé 17,18 . Les essais cliniques randomisés semblent montrer que les succédanés de sucre aident au contrôle du poids comparé aux sucres 18 26 . ...
... aspartame, saccharine, glycosides de stéviol), ne sont pas considérées comme des alternatives plus saines 17 , en raison d'un manque d'évidences claires sur leurs effets à long terme sur la santé 17,18 . Les essais cliniques randomisés semblent montrer que les succédanés de sucre aident au contrôle du poids comparé aux sucres 18 26 . Ces conditions sont liées, entre autres, à la scolarité, le revenu, l'occupation professionnelle, le logement, l'exposition aux polluants environnementaux, l'accès aux services essentiels, l'accès aux soins, la famille et le soutien social, la sécurité, etc. [25][26][27] . ...
Technical Report
Full-text available
Recommandations visant à limiter les inégalités sociales de santé issues de l’analyse des écrits scientifiques disponibles : • Mettre en avant en premier lieu : 1) la promotion de l’accessibilité physique à l’eau et la restriction de l’accès aux boissons sucrées dans les établissements publics et toutes les communautés, et 2) la réduction de la quantité de sucre et la taille des portions des boissons sucrées, • En cas de taxation des boissons sucrées : 1) attribuer les revenus générés par la taxe à des mesures structurelles destinées aux populations socio-économiquement plus défavorisées (p. ex. repas et collations de haute valeur nutritive et gratuits dans les écoles, accès gratuit à l’eau) (mesures en partie évoquées dans le Plan), 2) taxer aussi les jus de fruits purs, cafés/thés sucrés, ainsi que les boissons « diètes », et 3) encourager la reformulation des boissons sucrées par les fabricants via une taxation progressive (p. ex. taxe de 10 % si la boisson contient 0-50g/l de sucre et 20 % si >50g/l), • Étudier les effets des interventions mises en place sur les inégalités sociales en matière de la consommation des boissons sucrées, car les données probantes sont rares à ce jour, et • Poursuivre les efforts visant à 1) offrir des repas scolaires de haute valeur nutritive à tous les enfants, 2) offrir un accès universel aux soins et services dentaires, et 3) réduire la pauvreté.
... While use of NNS can help to significantly reduce the sugar content of products , there are still many concerns about the use of NNS. These include evidence suggesting that NNS intakes can impact the gut microbiota and cause neuroendocrine effects (Toews et al., 2019;Deo et al., 2020;Moriconi et al., 2020), the low methodological quality of current evidence demonstrating potential health benefits of NNS intake (Toews et al., 2019), and conflict of interest with the food industry declared in studies about NNS (Mandrioli, Kearns & Bero, 2016). Also, there is inconclusive evidence of very low certainty regarding the effects of NNS consumption in people with diabetes (Lohner et al., 2020), target population for which the use of NNS is frequently J o u r n a l P r e -p r o o f recommended. ...
... While use of NNS can help to significantly reduce the sugar content of products , there are still many concerns about the use of NNS. These include evidence suggesting that NNS intakes can impact the gut microbiota and cause neuroendocrine effects (Toews et al., 2019;Deo et al., 2020;Moriconi et al., 2020), the low methodological quality of current evidence demonstrating potential health benefits of NNS intake (Toews et al., 2019), and conflict of interest with the food industry declared in studies about NNS (Mandrioli, Kearns & Bero, 2016). Also, there is inconclusive evidence of very low certainty regarding the effects of NNS consumption in people with diabetes (Lohner et al., 2020), target population for which the use of NNS is frequently J o u r n a l P r e -p r o o f recommended. ...
Article
This study investigated the use of added sugars and non-nutritive sweeteners (NNS) in 4,805 packaged foods (including non-alcoholic beverages) sold in a major supermarket in Brazil. The ingredient lists of all products were searched for the presence of added sugars and NNS. The added sugar content was estimated and compared between products containing added sugar, with and without NNS. Using criteria set by the new Brazilian food label rules, we determined whether foods with added sugars and NNS were classified as “high in added sugar”. Most products (66.7%) contained at least one type of sweetener (added sugars or NNS). Of the products containing NNS (n = 597), 81.5% also contained added sugar. Products containing both NNS and added sugar ingredients showed a lower overall added sugar content than products containing added sugars only. However, for a few food categories (chocolates, dairy and non-dairy dessert mixes and candies), the added sugar content did not differ significantly between products with and without NNS. Sixty-three percent of products containing both added sugar and NNS were classified as “high in added sugar”.
... Artificial sweeteners reduce the risk of dental caries. However, there are mixed findings (negative, neutral, and positive) regarding the impact on weight, glycemic control, and cardiovascular disease12 Contains artificial colors and sweeteners. The impact on human health remains controversial (as briefly discussed above). ...
Article
Full-text available
A 62-year-old man with a past medical history of recently diagnosed type II diabetes mellitus presented for multiple episodes of nephrolithiasis after stopping Diet Mountain Dew ingestion. Stone analysis confirmed calcium oxalate stones. It was theorized that the high citrate in Diet Mountain Dew was protective against his newly recurrent nephrolithiasis. For lifestyle preference, the patient chose lemonade-flavored Crystal Light—known to be high in citrate—instead of potassium citrate 30—40 mEq supplementation. To date, the patient’s nephrolithiasis has not recurred. Potassium citrate is a preventive strategy against calcium oxalate stones in patients with suspected or confirmed hypocitraturia. Citrate binds calcium, therefore, preventing the interaction between calcium and oxalate. Alternative supplementation strategies, such as citrus-flavored sodas (eg, Diet Mountain Dew), powdered drinks (eg, Crystal Light), and natural juices (eg, lemon juice), may be plausible alternatives to potassium citrate. Patient lifestyle and the risks and benefits to a particular supplemental choice must be considered for every patient.
... Despite the large body of research on alternatives for SSB, their impact on body weight remains a topic of sustained debate due to inconsistent findings. Available randomized control trials (RCTs) and meta-analyzes of RCTs on weight loss generally indicate a beneficial impact of consuming LNCB instead of SSB (9)(10)(11)(12)(13). In contrast, meta-analyzes of observational studies observed either no association (9) or a modest positive association between LNCB consumption and body mass index (BMI) (12,13). ...
Article
Full-text available
Background/Methods Prospective studies investigating sweet beverages and body weight associations show inconsistent results. Within the SWEET project, we examined prospective dose-response associations of sugar-sweetened beverages (SSB), low/no-calorie beverages (LNCB), and fruit juice with body weight-related outcomes among 78,286 Dutch adults followed for ~4 years. Baseline intakes were assessed using a validated food-frequency questionnaire (FFQ) with 150 ml representing a standard serving. Outcome variables were body weight change, waist circumference change, overweight/obesity, and abdominal obesity. Associations were investigated by using linear and non-linear dose-response analysis, as well as substitution models while adjusting for multiple socio-demographic, lifestyle, health, and dietary variables. Results Participants were 46 ± 13 (mean ± SD) years old and 60% were women. Adjusted dose-response analyzes indicated an association between SSB and LNCB, and both body weight (+0.02 kg/year; SE 0.01 and +0.06 kg/year; SE 0.01) and waist circumference changes (+0.04 cm/year; SE: 0.01 and +0.11 cm/year; SE: 0.01). Associations for overweight/obesity and abdominal obesity incidence were +3% (95%CI: 1.00–1.06) and +2% (95%CI: 0.99–1.06) for SSB and +8% (95%CI: 1.06–1.11) and +5% (95%CI: 1.03–1.07) for LNCB, respectively. Substitution of SSB with LNCB was associated with higher weight change (+0.04 kg/year), waist circumference change (+0.09 cm/year), overweight/obesity incidence (+6%), but not abdominal obesity incidence. For fruit juice, we observed beneficial associations for intake levels below ~1 serving/day with weight, waist circumference change, and overweight/obesity incidence, and no association with abdominal obesity. Subsequent substitution analyzes indicated a small beneficial association for the replacement of SSB with fruit juice on weight (−0.04 kg/year) and waist circumference (−0.04 cm/year), but not with other outcomes. Conclusions Overall, our results suggest that habitual consumption of both SSB and LNCB may adversely affect weight-related outcomes. In contrast, fruit juice consumption <150 ml may be beneficial with respect to weight and waist circumference.
Article
BACKGROUND Adverse associations of low- and no-calorie sweetened beverages (LNCSB) with cardiometabolic outcomes in observational studies may be explained by reverse causality and residual confounding. PURPOSE To address these limitations we used change analyses of repeated measures of intake and substitution analyses to synthesize the association of LNCSB with cardiometabolic outcomes. DATA SOURCES MEDLINE, Embase, and the Cochrane Library were searched up to 10 June 2021 for prospective cohort studies with ≥1 year of follow-up duration in adults. STUDY SELECTION Outcomes included changes in clinical measures of adiposity, risk of overweight/obesity, metabolic syndrome, type 2 diabetes (T2D), cardiovascular disease, and total mortality. DATA EXTRACTION Two independent reviewers extracted data, assessed study quality, and assessed certainty of evidence using GRADE. Data were pooled with a random-effects model and expressed as mean difference (MD) or risk ratio (RR) and 95% CI. DATA SYNTHESIS A total of 14 cohorts (416,830 participants) met the eligibility criteria. Increase in LNCSB intake was associated with lower weight (5 cohorts, 130,020 participants; MD −0.008 kg/year [95% CI −0.014, −0.002]). Substitution of LNCSB for sugar-sweetened beverages (SSB) was associated with lower weight (three cohorts, 165,579 participants; MD, −0.12 [−0.14, −0.10,] kg/y) and lower incidence of obesity (OB) (one cohort, 15,765 participants; RR 0.88 [95% CI 0.88, 0.89]), coronary heart disease (six cohorts, 233,676 participants; 0.89 [0.81, 0.98]), cardiovascular disease mortality (one cohort, 118,363 participants; 0.95 [0.90, 0.99]), and total mortality (one cohort, 118,363 participants; 0.96 [0.94, 0.98]) with no adverse associations across other outcomes. Substitution of water for SSB showed lower weight (three cohorts, 165,579 participants; MD −0.10 kg/year [−0.13, −0.06]), lower waist circumference (one cohort, 173 participants; −2.71 cm/year [−4.27, −1.15]) and percent body fat (one cohort, 173 participants; −1.51% per year [−2.61, −0.42]), and lower incidence of OB (one cohort, 15,765 participants; RR 0.85 [0.75, 0.97]) and T2D (three cohorts, 281,855 participants; 0.96 [0.94, 0.98]). Substitution of LNCSB for water showed no adverse associations. LIMITATIONS The evidence was low to very low certainty owing to downgrades for imprecision, indirectness, and/or inconsistency. CONCLUSIONS LNCSB were not associated with cardiometabolic harm in analyses that model the exposure as change or substitutions. The available evidence provides some indication that LNCSB in their intended substitution for SSB may be associated with cardiometabolic benefit, comparable with the standard of care, water.
Article
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Replacing sugar with non-nutritive artificial sweeteners (NAS) is a popular dietary choice for the prevention and management of metabolic syndrome and its comorbidities. However, evidence in human trials is conflicted regarding the efficacy of this strategy and whether NAS may counterintuitively promote, rather than prevent, metabolic derangements. The heterogeneity in outcomes may stem in part from microbiome variation between human participants and across research animal vivaria, leading to differential interactions of NAS with gut bacteria. An increasing body of evidence indicates that NAS can alter the mammalian gut microbiome composition, function, and metabolome, which can, in turn, influence host metabolic health. While there is evidence for microbiome-mediated metabolic shifts in response to NAS, the mechanisms by which NAS affect the gut microbiome, and how the microbiome subsequently affects host metabolic processes, remain unclear. In this viewpoint, we discuss data from human and animal trials and provide an overview of the current evidence for NAS-mediated microbial and metabolomic changes. We also review potential mechanisms through which NAS may influence the microbiome and delineate the next steps required to inform public health policies.
Book
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The revised edition of the Handbook offers the only guide on how to conduct, report and maintain a Cochrane Review. The second edition of The Cochrane Handbook for Systematic Reviews of Interventions contains essential guidance for preparing and maintaining Cochrane Reviews of the effects of health interventions. Designed to be an accessible resource, the Handbook will also be of interest to anyone undertaking systematic reviews of interventions outside Cochrane, and many of the principles and methods presented are appropriate for systematic reviews addressing research questions other than effects of interventions. This fully updated edition contains extensive new material on systematic review methods addressing a wide-range of topics including network meta-analysis, equity, complex interventions, narrative synthesis, and automation. Also new to this edition, integrated throughout the Handbook, is the set of standards Cochrane expects its reviews to meet. Written for review authors, editors, trainers and others with an interest in Cochrane Reviews, the second edition of The Cochrane Handbook for Systematic Reviews of Interventions continues to offer an invaluable resource for understanding the role of systematic reviews, critically appraising health research studies and conducting reviews.
Article
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Background Food products containing non-nutritive sweeteners (NNSs) instead of sugar have become increasingly popular in the last decades. Their appeal is obviously related to their calorie-free sweet taste. However, with the dramatic increase in their consumption, it is reasonable and timely to evaluate their potential health benefits and, more importantly, potential adverse effects. The main aim of this scoping review was to map the evidence about health outcomes possibly associated with regular NNS consumption by examining the extent, range, and nature of research activity in this area. Methods We systematically searched Ovid MEDLINE, EMBASE and the Cochrane CENTRAL databases for studies on NNSs (artificial sweeteners or natural, non-caloric sweeteners, either used individually or in combination) using text terms with appropriate truncation and relevant indexing terms. All human studies investigating any health outcomes of a NNS intervention or exposure were eligible for inclusion. No studies were excluded based on language, study design or methodological quality. Data for each health outcome were summarized in tabular form and were discussed narratively. Results Finally, we included 372 studies in our scoping review, comprising 15 systematic reviews, 155 randomized controlled trials (RCTs), 23 non-randomized controlled trials, 57 cohort studies, 52 case-control studies, 28 cross sectional studies and 42 case series/case reports. In healthy subjects, appetite and short term food intake, risk of cancer, risk of diabetes, risk of dental caries, weight gain and risk of obesity are the most investigated health outcomes. Overall there is no conclusive evidence for beneficial and harmful effects on those outcomes. Numerous health outcomes including headaches, depression, behavioral and cognitive effects, neurological effects, risk of preterm delivery, cardiovascular effects or risk of chronic kidney disease were investigated in fewer studies and further research is needed. In subjects with diabetes and hypertension, the evidence regarding health outcomes of NNS use is also inconsistent. Conclusions This scoping review identifies the needs for future research to address the numerous evidence gaps related to health effects of NNSs use.It also specifies the research questions and areas where a systematic review with meta-analyses is required for the proper evaluation of health outcomes associated to regular NNSs consumption.
Article
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Background: Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects. Methods: We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points. Results: From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference -0.37 kg/m(2); 95% confidence interval [CI] -1.10 to 0.36; I(2) 9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; I(2) 0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome. Interpretation: Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners. Protocol registration: PROSPERO-CRD42015019749.
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Introduction Low-calorie sweetener use for weight control has come under increasing scrutiny as obesity, especially abdominal obesity, remain entrenched despite substantial low-calorie sweetener use. We evaluated whether chronic low-calorie sweetener use is a risk factor for abdominal obesity. Participants and Methods We used 8268 anthropometric measurements and 3096 food diary records with detailed information on low-calorie sweetener consumption in all food products, from 1454 participants (741 men, 713 women) in the Baltimore Longitudinal Study of Aging collected from 1984 to 2012 with median follow-up of 10 years (range: 0–28 years). At baseline, 785 were low-calorie sweetener non-users (51.7% men) and 669 participants were low-calorie sweetener users (50.1% men). Time-varying low-calorie sweetener use was operationalized as the proportion of visits since baseline at which low-calorie sweetener use was reported. We used marginal structural models to determine the association between baseline and time-varying low-calorie sweetener use with longitudinal outcomes—body mass index, waist circumference, obesity and abdominal obesity—with outcome status assessed at the visit following low-calorie sweetener ascertainment to minimize the potential for reverse causality. All models were adjusted for year of visit, age, sex, age by sex interaction, race, current smoking status, dietary intake (caffeine, fructose, protein, carbohydrate, and fat), physical activity, diabetes status, and Dietary Approaches to Stop Hypertension score as confounders. Results With median follow-up of 10 years, low-calorie sweetener users had 0.80 kg/m² higher body mass index (95% confidence interval [CI], 0.17–1.44), 2.6 cm larger waist circumference (95% CI, 0.71–4.39), 36.7% higher prevalence (prevalence ratio = 1.37; 95% CI, 1.10–1.69) and 53% higher incidence (hazard ratio = 1.53; 95% CI 1.10–2.12) of abdominal obesity than low-calorie sweetener non-users. Conclusions Low-calorie sweetener use is independently associated with heavier relative weight, a larger waist, and a higher prevalence and incidence of abdominal obesity suggesting that low-calorie sweetener use may not be an effective means of weight control.
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This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of non-nutritive sweeteners for diabetes mellitus.
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Background: The influence of artificial sweeteners on metabolic diseases is controversial. Artificially sweetened beverages have been associated with an increased risk of type 2 diabetes (T2D) but biases and reverse causation have been suspected to have influenced the observed association. In addition, it has been suggested that investigation into the relationship between the frequency and duration of the consumption of packet or tablet artificial sweeteners and T2D risk is necessary. Methods: We used data from 61,440 women in the prospective E3N-European Prospective Investigation into Cancer and Nutrition study, conducted between 1993 and 2011. We estimated hazards ratios (HRs) and 95% CIs of T2D risk associated with both the frequency and the duration of use of artificial sweeteners consumed in packets or tablets. Results: Compared to "never or rare" consumers of artificial sweeteners, those using them "always or almost always" had an increased risk of T2D (HR = 1.83 [95% CI 1.66-2.02] in the multivariate model [MM], HR = 1.33 [95% CI 1.20-1.47] when further adjusted for body mass index, BMI). Women consuming artificial sweeteners in packets or tablets for more than 10 years also had an increased risk of T2D compared to never or rare users (HR = 2.10 [95% CI 1.83-2.40] in the MM and HR = 1.15 [95% CI 1.00-1.33] when adjusted for BMI, respectively). Conclusions: Our data suggest that both a higher frequency and a longer consumption of artificial sweeteners in packets or tablets was associated with T2D risk, independently of major T2D risk factors, but partially mediated by adiposity. A precautionary principle should be applied to the promotion of these products that are still largely recommended as healthy sugar substitutes.