WHO NSS meta analysis

Health effects of the use

of non-sugar sweeteners

A systematic review and meta-analysis

Magali Rios-Leyvraz and Jason Montez

Health effects of the use of non-sugar sweeteners

A systematic review and meta-analysis

Magali Rios-Leyvraz and Jason Montez

Health effects of the use of non-sugar sweeteners: a systematic review and meta-analysis/ Magali Rios-Leyvraz, Jason Montez

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Contents

Acknowledgements v Abbreviations vi Executive Summary 1 1. Background 2

2. Methods

2.1

Eligibility criteria 3

2.1.1 Participants 3
2.1.2 Interventions and exposures 3
2.1.3 Comparators 4
2.1.4 Outcomes 4
2.1.5 Study design 4
2.1.6 Duration 5
2.1.7 Other 5

Search strategy 5 Selection process 5 Data extraction 5 Assessment of risk of bias 6 Data analysis 6 Assessment of quality of evidence 7

Adults

3.1.1 Adiposity 10
3.1.2 Type 2 diabetes 18
3.1.3 All-cause mortality 21
3.1.4 Cardiovascular diseases 21
3.1.5 Cancer 26
3.1.6 Chronic kidney disease 29
3.1.7 Eating behaviour 30
3.1.8 Sweet preference 33
3.1.9 Dental caries 35
3.1.10 Mood 35
3.1.11 Neurocognition 35
3.1.12 Behaviour 36

2.2 2.3 2.4 2.5 2.6 2.7

3. Results

3.1

iii Contents

3.3

4. Discussion Annexes

Annex 1.

Annex 2. Annex 3. Annex 4. Annex 5. Annex 6. Annex 7. Annex 8. Annex 9. Annex 10. Annex 11.

Search strategies 49

MEDLINE, MEDLINE In-Process and Other Non-Indexed
Citations (Ovid), and Embase (Ovid) 49

Cochrane CENTRAL 50 Outcomes reported by study design and population 52 Characteristics of included studies 53 Characteristics of ongoing/registered trials 83 Adjustments for potential confounders in cohort studies 85 Risk of bias assessment 92 GRADE evidence profiles 98 Funnel plots 114 Supplementary figures 121 Excluded studies 159 Differences in study selection between original review

and current update 163

167

References

3.2

Children 36

3.2.1 Adiposity 36
3.2.2 Type 2 diabetes 36
3.2.3 Cardiovascular diseases 37
3.2.4 Cancer 37
3.2.5 Eating behaviour 37
3.2.6 Sweet preference 37
3.2.7 Dental caries 38
3.2.8 Mood 38
3.2.9 Behaviour 38
3.2.10 Neurocognition 38
3.2.11 Asthma 39
3.2.12 Allergies 39

Pregnant women 39

3.3.1 Maternal outcomes 39
3.3.2 Birth outcomes 39
3.3.3 Health effects in offspring 40
3.3.4 Additional outcomes 41

iv Health effects of the use of non-sugar sweeteners

Acknowledgements

This document is an update of a systematic review that was conducted by Ingrid Töews, Szimonetta Lohner, Daniela Küllenberg de Gaudry, Harriet Sommer and Joerg J Meerpohl
and published in 2019 (1). Special thanks are due to Ingrid Töews and Szimonetta Lohner for sharing data and R codes from the original systematic review, to Andrew Reynolds for helping to conduct searches of Medline and Embase, and to Lee Hooper and Russell de Souza for feedback and guidance on analytical methods. Valuable inputs and critical review were provided by the members of the WHO Nutrition Guidance Expert Advisory Group Subgroup on Diet and Health: Hayder Al-Domi, John H. Cummings, Ibrahim Elmadfa, Lee Hooper, Shiriki Kumanyika, Mary L’Abbé, Pulani Lanerolle, Duo Li, Jim Mann, Joerg Meerpohl, Carlos Monteiro, Laetitia Ouedraogo Nikièma, Harshpal Singh Sachdev, Barbara Schneeman, Murray Skeaff, Bruno Fokas Sunguya,
HH (Esté) Vorster.

The financial support provided by the Government of Japan for the undertaking of the systematic review and the production of this document is gratefully acknowledged.

v Acknowledgements

Abbreviations

ADI acceptable daily intake
BMI body mass index
CI confidence interval
GRADE Grading of Recommendations Assessment, Development and Evaluation HbA1c glycated haemoglobin

HDL high-density lipoprotein
HOMA-IR homeostatic model assessment of insulin resistance HR hazard ratio
LDL low-density lipoprotein
MD mean difference
NCD noncommunicable disease
NHANES National Health and Nutrition Examination Survey NSS non-sugar sweeteners
NUGAG Nutrition Guidance Expert Advisory Group
OR odds ratio
RCT randomized controlled trial
RR relative risk
SE standard error
SMD standardized mean difference
SSB sugar-sweetened beverage
WHO World Health Organization

vi Health effects of the use of non-sugar sweeteners

Executive summary

A 2019 systematic review on intake of non-sugar sweeteners (NSS) in adults and children was updated and expanded to include studies in which NSS were not specified by name and studies of effects of NSS on pregnant women published through July 2021. A total of 283 studies were included in the review. Meta-analyses focused on randomized controlled trials, prospective cohort studies and case–control studies assessing cancer, and certainty in results was assessed via GRADE (Grading of Recommendations Assessment, Development and Evaluation). Results for key outcomes in adults (including pregnant women) are summarized in the figure below. In addition, a single randomized controlled trial conducted in children reported decreases in several measures of adiposity, but no significant effects or associations were observed in meta-analyses.

Randomized controlled trials Cohort/case–control studies

Adiposity

ä Body weight –0.71 kg (low)
ä BMI –0.14 kg/m2 (low)

Ø Other measures (waist-to-hip ratio,

waist circumference, fat/lean mass)

Type 2 diabetes

Ø Intermediate markers (glucose, insulin, HOMA-IR, HbA1c)

All-cause mortality

No data

Cardiovascular diseases

ã Total:HDL cholesterol +0.09 (moderate) Ø Blood pressure, cholesterol (total, LDL,

HDL), triglycerides)

Cancer

No data

Total energy intake (kJ/day)

ä Energy intake –569 (low) Sugars intake (g/day)

ä Sugars intake –38 (low)

Pregnancy

No data

Mostly in NSSÒsugars

Adiposity

ã Incident obesity HR 1.76 (low)
ã BMI +0.14 kg/m2 (very low)

Ø Other measures

Type 2 diabetes

ã Disease (beverage) HR 1.23 (low)
ã Disease (tabletop) HR 1.34 (low)
ã High fasting glucose HR 1.21 (low)

Ø Other measures

All-cause mortality

ã Mortality HR 1.12 (very low)

Cardiovascular diseases

ã CVD mortality HR 1.19 (low)
ã CV events HR 1.32 (low)

Ø CHD (very low)

ã Stroke HR 1.19 (low)
ã Hypertension HR 1.13 (low)

Cancer

Ø Mortality (very low)
Ø Incidence: any type (very low)

ã Bladder cancer OR 1.31

(very low)

Total energy intake (kJ/day)

No data

Sugars intake (g/day)

No data

Pregnancy

ã Preterm birth HR 1.25 (low)

Mostly in saccharin

BMI: body mass index; CHD: coronary heart disease; CV: cardiovascular; CVD; cardiovascular disease; HDL: high-density lipoprotein; HOMA-IR: Homeostatic Model Assessment of Insulin Resistance; HR: hazard ratio; LDL: low-density lipoprotein; OR: odds ratio; tabletop = NSS added to foods or beverages by the consumer.

Note: Text in parentheses refers to certainty in the evidence as assessed by GRADE. “Mostly in” refers to results of subgroup analysis; “NSSÒsugars” refers to studies in which NSS were compared with sugars. ã= increased effect,ä= decreased effect, Ø = no effect.

1 Executive summary

1. Background

Consumption of free sugars has been linked to escalating rates of overweight and obesity (2, 3), as well as development of diet-related noncommunicable diseases (NCDs), including dental caries, type 2 diabetes, cardiovascular diseases and cancer (4–7).

As part of global efforts to stem the tide of obesity and diet-related NCDs, the World Health Organization (WHO) has issued guidance on intake of sugars, recommending that intake be significantly reduced (8). With the current focus on reducing intake of free sugars, interest in non-sugar sweeteners (NSS) as a possible alternative has intensified.

NSS are no-calorie or low-calorie artificial and natural sweeteners that have been developed as an alternative to sugars. They are widely used as ingredients in pre-packaged foods and beverages, and are added to foods and beverages by consumers (9–11). NSS include synthetically derived chemicals and natural extracts that may or may not be chemically modified. Because of their ability to impart sweet taste without calories, some argue that they can help to prevent overweight and obesity. However, others suggest that they may increase risk. From an oral health standpoint, NSS might reduce the risk of dental caries if used as a replacement for sugar. Although commercially available NSS are tested for toxicity before being introduced into the market, potential long-term effects on health of consuming NSS at levels below the acceptable daily intake (ADI) established by authoritative bodies are not as well characterized.

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. This review attempts to address both any inherent health effects of NSS (i.e. health effects attributable to NSS regardless of comparator), as well as health effects of NSS when compared with sugars or water, when consumed at safe levels as established by authoritative bodies.

2 Health effects of the use of non-sugar sweeteners

2. Methods

The protocol for the current review was modified slightly from that used in the original review (1). It was developed in accordance with the WHO guideline development process (12), the PRISMA statement for preferred reporting items for systematic review and meta-analysis protocols (13– 15), and the Cochrane handbook for systematic reviews of interventions (16).

2.1 Eligibility criteria

2.1.1 Participants

We included studies conducted in generally healthy populations of adults (≥18 years of age), children (<18 years of age) or pregnant women. Studies conducted in overweight, obese or mixed- weight populations were included, but studies conducted exclusively in pre-diabetic or diabetic populations were excluded. We also excluded studies conducted exclusively in populations with other diseases (except for case–control studies with hospital patient controls), as well as in vitro and animal studies.
2.1.2 Interventions and exposures

The interventions and exposures of interest were any type of NSS (excluding sugar alcohols and natural caloric sweeteners), whether specified by name or not, and whether used alone or in combination with other NSS.1

We included studies that reported use of NSS within the ADI as established by the Joint FAO/ WHO Expert Committee on Food Additives (JECFA) (17) (Table 1) and excluded studies in which NSS intake explicitly exceeded the ADI. Studies were included if it was unclear whether an ADI had been exceeded (e.g. in prospective cohort studies, where exposures to NSS are generally not reported quantitatively in terms of amount of NSS, but rather in terms of servings of food or beverage containing NSS per day or week).

Table 1. ADI of NSS as established by JECFA

Acesulfame K 15

Advantame 5

Aspartame 40

Cyclamate 11

Neotame 0.3

Saccharin 15

Steviol glycosides 4

Sucralose 5

ADI: acceptable daily intake; JECFA: Joint FAO/WHO Expert Committee on Food Additives; NSS: non-sugar sweeteners.

1 This review uses the same definition for non-sugar sweeteners as in the original review (1) – that is, NSS include all artificial sweeteners and natural non-caloric sweeteners. They do not include sugar alcohols or modified sugars. For simplicity, “NSS” is used throughout the main body of this document to refer to non-sugar sweeteners regardless of what they were called in the individual studies (e.g. non-nutritive sweeteners, artificial sweeteners, low/no-calorie sweeteners).

Sweetener

ADI (mg/kg of body weight)

3 2. Methods

2.1.3 Comparators

We included studies that compared NSS consumption with no or lower doses of NSS consumption. We included trials that compared the intervention with any type of sugar, placebo, plain water or no intervention. Trials with concomitant interventions were included, provided that the concomitant interventions were similar and equally balanced between the comparison arms. We did not include studies that only compared one or more NSS to one another, without also comparing with a sugar, placebo, plain water or no intervention.

2.1.4 Outcomes

The health outcomes of interest for adults and children were identified by the WHO Nutrition Guidance Expert Advisory Group (NUGAG) Subgroup on Diet and Health as:

¢¢measures of adiposity (e.g. body weight, body mass index [BMI], overweight/obesity, fat and lean mass);

¢¢type 2 diabetes and pre-diabetes (incidence and intermediate markers of glycaemic control); ¢¢cardiovascular diseases (incidence and intermediate markers, such as blood pressure and

lipids); ¢¢cancer;

¢¢dental caries;
¢¢chronic kidney disease;
¢¢eating behaviour (e.g. appetite, satiety, energy intake); ¢¢sweet preference (e.g. subjective measures, sugars intake); ¢¢neurocognition;
¢¢mood and behaviour; and
¢¢asthma and allergies (for children only).

In addition, we included all-cause mortality; cause-specific mortality related to cardiovascular diseases and cancer; and pregnancy and birth outcomes for pregnant women, based on outcomes specified in this review for children, as well as those previously identified for previous pregnancy reviews (including gestational diabetes, birthweight and gestation-related outcomes). We also included any outcomes assessed to be adverse outcomes or events that were not included in the list of outcomes of interest.

2.1.5 Study design

Randomizedcontrolledtrials(RCTs)(includingparallel,clusterandcrossovertrials),nonrandomized controlled trials, prospective cohort studies, case–control studies and cross-sectional studies were included in the review. Because there was ample evidence from RCTs and prospective cohort studies for most major outcomes of interest, results from these study designs and case–control studies reporting on cancer outcomes1 were included in the main meta-analyses and assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.2 Results from other study types were pooled in secondary analyses and/or summarized narratively as supplementary data (when data from RCTs and/or prospective cohort studies were not available) and were not assessed using GRADE. All other study designs, including nonrandomized

1 A majority of studies reporting on cancer outcomes are of case–control design, and therefore were included in meta-analyses and GRADE assessment to avoid excluding this significant body of evidence. Case–control studies reporting on other outcomes were not included in meta-analysis and GRADE assessment.

2 https://www.gradeworkinggroup.org/

4 Health effects of the use of non-sugar sweeteners

controlled trials, ecological studies, case series and case reports, reviews, and meta-analyses were excluded.

2.1.6 Duration

Studies with a minimum intervention duration or follow-up of 13 days for blood lipid outcomes, 1 year for disease incidence outcomes (i.e. incident cancer, cardiovascular diseases, type 2 diabetes), and 7 days for all other outcomes in adults and children were included. Outcomes for pregnant women required assessment of NSS exposure during pregnancy without restrictions on follow-up time.
2.1.7 Other

There were no restrictions by type of setting, language or date of publication.

2.2 Search strategy

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.

The search strategies are shown in Annex 1.
2.3 Selection process

After collection of all potential records and removal of duplicates, all the titles, abstracts and full texts were screened for eligibility in duplicate by two researchers. The data management software Covidence2 was used for the selection process. Any disagreement on the exclusion or inclusion of a record between the two reviewers was resolved by discussion.
2.4 Data extraction

Data extraction was done in two steps. In the first step, the basic study information, such as study design, population, country, funding, intervention, comparator, outcome, sample size and summary of effect, were extracted for all studies. In the second step, the full information was extracted for a subset of studies, depending on the study designs available for each outcome. The order of priority for full data extraction was RCTs, prospective cohort studies, nonrandomized controlled trials, case–control studies and cross-sectional studies.

If multiple interventions were conducted in a study, the comparisons allowing the best estimate of the effect of NSS were selected. Data were not extracted for arms of trials with multifactorial interventions that were not matched for everything except NSS across arms of the trial. If outcomes were measured at multiple time points, the time points nearest to the beginning and the end of the intervention were selected for experimental studies, or the longest follow-up for observational studies. If a single study was published in multiple articles, the most complete and recent estimates were extracted.

1 Including MEDLINE In-Process & Other Non-Indexed Citations 2 https://www.covidence.org/

5 2. Methods

Because of slight baseline imbalance in most of the RCTs included in the review (concomitant with relatively small effect sizes), we extracted change from baseline values for each arm in a trial.

For prospective cohort studies reporting adjusted results from multiple models, the effect sizes corresponding to the most adjusted models were extracted. In prospective cohort studies where the upper quantile was clearly above the ADI for a particular NSS, data were extracted from the next lower quantile to be used for comparison with the lowest, referent quantile. In prospective cohort studies, when effect sizes were reported continuously, the effect size reporting per serving size was used. If the only effect sizes available were not per serving size (e.g. per fluid ounce, per N mL), they were scaled to a serving size of 300 mL.

If data were ambiguous, not reported in a usable format, missing or not yet published (in the case of ongoing studies identified from trial registries), we contacted the responsible researcher via email. If data were only available from figures, they were extracted using the validated software Plot Digitizer.1

2.5 Assessment of risk of bias

Risk of bias in RCTs was assessed using the Cochrane risk of bias (ROB) tool (16). In assessing risk of bias in RCTs, emphasis was placed on adequate randomization, and limited loss to follow-up (incomplete outcome data) and selective reporting. Blinding of participants would have been difficult in many studies, given different behavioural advice, and the obvious taste differences between sugars, water and NSS. Risk of bias related to blinding of participants was assessed as:

¢¢high in studies comparing clear differences in advice, or comparing water with NSS;

¢¢low in studies delivering NSS via capsule; and

¢¢unclear where NSS were compared with sugars, as it is not clear whether participants would have been able to taste the difference in foods or beverages.

Risk of bias in prospective cohort studies and case–control studies was assessed by the risk of bias in nonrandomized studies of interventions (ROBINS-I) method (18) and confirmed with the Newcastle–Ottawa Scale.2 Risk of bias assessments using each method were largely in agreement, and Newcastle–Ottawa Scale results were used in assessing the quality of the evidence for observational studies via the GRADE framework.3

Publication bias was assessed with enhanced funnel plots and Egger’s test when data from at least 10 studies could be meta-analysed (16, 19).
2.6 Data analysis

Data transformations and imputations were done according to the Cochrane handbook for systematic reviews of interventions (16) and following the recommendations of Borenstein et al. (20). Whenever possible, the different effect sizes reported were transformed to a common effect size to allow meta-analysis. If standard deviations were missing, they were calculated from standard errors, confidence intervals, P values or t values; approximated using the Taylor series expansion; or imputed from the standard errors reported in the same study. Where the standard deviation or equivalent was not reported for the change from baseline, we derived a correlation coefficient from well-conducted trials reporting the same outcome for the same or very similar intervention (16). When multiple trials provided data and the calculated correlation coefficients were very similar within an arm of the trial, we averaged them. When the correlation coefficients across arms (i.e. across intervention and control arms) were similar, we averaged these into an outcome-specific single correlation coefficient to be used on any arm in a trial for that outcome.

1 http://plotdigitizer.sourceforge.net
2 http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp 3 https://www.gradeworkinggroup.org/

6 Health effects of the use of non-sugar sweeteners

When we were unable to identify relevant studies from which to derive a correlation coefficient, a value of 0.5 was selected, and sensitivity analyses using values of 0.25 and 0.75 were conducted to assess the impact on the results.

If comparable outcome data from two or more studies were available, we conducted random effects meta-analyses using the DerSimonian–Laird method (21). Meta-analyses were conducted separately for adults, children and pregnant women, and, within each population, separately for RCTs, prospective cohort studies and case–control studies. In multi-arm trials, arms were combined for the main meta-analyses when they included:

¢¢two or more relevant comparators to NSS (i.e. sugar-sweetened beverages [SSBs] and water controls); or

¢¢two or more NSS interventions (e.g. multiple doses of the same NSS or multiple, different NSS).

Trial arms were combined using the formula for combining groups recommended in the Cochrane handbook for systematic reviews of interventions (16). Heterogeneity was assessed with the I2 statistic. Sources of heterogeneity and confounding were explored using pre-specified subgroup, sensitivity and meta-regression analyses. A priori analyses included differences in effects between:

¢¢normal-weight and overweight populations;

¢¢comparators of NSS (i.e. water, sugar, nothing/placebo);

¢¢study designs (including weight loss vs non–weight loss studies);

¢¢publication types (e.g. poster/abstract, journal article);

¢¢participant consumption patterns of foods and beverages containing free sugars and foods and beverages containing NSS;

¢¢durations of the intervention/exposure; and
¢¢risks of bias in the studies.
Studies that could not be meta-analysed were reported narratively.

For the 1997 study by Blackburn et al. (22), the data reported for the longest follow-up (week 151) were used in all analyses except for subgroup analyses by study design (weight loss vs non– weight loss studies); for these analyses, the data reported at the end of the weight maintenance phase were used (week 71). In the original study by Engel et al. (2018) (23), standard deviations were erroneously reported as standard errors. A correction was issued in 2020 fixing this error (24), and values used in this review are the corrected values.

Statistical analyses were conducted with RAnalyticFlow (version 3.1.8) with the package meta.

2.7 Assessment of quality of evidence

The quality of (certainty in) the evidence was assessed using the GRADE framework.1 Certainty in the evidence was assessed as very low, low, moderate or high, based on risk of bias, inconsistency, indirectness and imprecision, as well as other considerations including possibility of publication bias and evidence of a dose–response relationship (in the case of observational studies).

1 https://www.gradeworkinggroup.org/

7 2. Methods

3. Results

From more than 8000 records identified, a total of 370 records, representing 283 unique studies conducted in adults, children, pregnant women or mixed populations, were included in this review:

¢¢50 RCTs
¢¢97 prospective cohort studies
¢¢47 case–control studies assessing cancer outcomes
¢¢5 nonrandomized controlled trials
¢¢69 cross-sectional studies
¢¢15 ongoing/registered trials (for which published results were not identified).

The flowchart of the study selection process is shown in Fig. 1. Studies were identified that assessed virtually all priority health outcomes for each population of interest, and the coverage of outcomes across study types is shown in Fig. 2 and in tabular form in Annex 2. Characteristics of included studies are shown in Annex 3 and of ongoing trials in Annex 4. Reasons for exclusion of studies can be found in Annex 10, and differences between this review and the original review can be found in Annex 11.

This review includes 45 RCTs conducted in adults, four in children, and one including both adults and children. No relevant trials in pregnant women were identified. Trial duration in adults (including follow-up post-intervention) ranged from 7 days to more than 3 years. Trials in adults were conducted in lean populations (n = 10), mixed-weight populations (n = 20) or exclusively overweight populations (n = 15). They were generally of mixed sex (n = 38), but one trial included males only, and five trials included females only (one trial did not specify). Eight of the trials conducted in adults were crossover trials; the remainder had a parallel design. Thirteen of the trials used an unspecified NSS in their intervention, 12 used aspartame, six used sucralose, three used stevia, one used saccharin, five used a mix of more than one NSS, one used advantame, and four tested multiple NSS separately (saccharin, aspartame, rebaudioside A/stevia, sucralose; sucralose, stevia; aspartame, acesulfame K). Trials in adults were conducted in Australia (n = 2), Denmark (n = 2), France (n = 2), Greece (n = 1), the Republic of Korea (n = 4), the Islamic Republic of Iran (n = 1), Latvia (n = 1), Mexico (n = 6), New Zealand (n = 2), Switzerland (n = 1), Thailand (n = 1), the United Kingdom (n = 7), the United States (n = 14) and multiple countries (n = 1).

The four RCTs in children were all of parallel design, conducted in mixed-sex populations (except for one conducted in females only), and lasted from 6 weeks to 18 months. Two trials used stevia in the intervention arm, one used a mix of sucralose and acesulfame K, and one used sucralose. One trial in children was conducted in each of India, Italy, the Netherlands and South Africa.

The single parallel trial conducted in adults and children included a mixed-sex population, used aspartame in the intervention, and was conducted in the United States.

Seventeen of the trials conducted in adults, two of the trials conducted in children, and the trial with both adults and children were either fully or partially funded by industry. Interventions included providing dietary advice (with or without the provision of food) to effect behaviour change (e.g. replacing sugar-sweetened foods and/or beverages with those that contained NSS or were unsweetened), using supplemental foods and beverages containing sugars or NSS, asking habitual users of NSS to discontinue use, and providing NSS in capsule form compared with a placebo. The focus of the trials was not always on assessing the effects of NSS; several trials had

8 Health effects of the use of non-sugar sweeteners

Fig. 1.

Flow chart of study identification and selection

Title and abstract screening

Full-text screening

205 records included from list of included and excluded studies from BMJ 2019 review

4 hand-searched

12 records identified from other systematic reviews

8237 records retrieved from searches

6840 records screened based on title and abstract

493 records included for full-text screening

Data extraction

370 records including 283 unique studies:

50 randomized controlled trials
97 prospective cohort studies
47 case–control studies
5 non-randomized controlled trials 69 cross-sectional studies

15 ongoing/registered trials

1397 duplicates excluded

6519 records excluded

321 records included for full-text screening

33 duplicates excluded

139 articles excluded because:

48 Wrong intervention/exposure 23 No outcome of interest
16 Wrong study/publication type 17 Study duration too short

10 Wrong study population 7 Wrong or no comparator 6 NSS too high
9 Duplicate

3 Full text not found

the primary goal of testing the effects of sugars and used NSS as a control. To reflect this, we refer to the results of trials as having achieved a higher intake of NSS in one or more arms, rather than explicitly increasing NSS intake or replacing sugars, for example. Additional detail about the RCTs can be found in Table A3.1 of Annex 3.

Significant concerns were noted regarding one RCT included in this review with respect to how data were reported, possible numerical errors, and unusual results for some outcomes (25). Sensitivity analyses, in which this trial was removed, did not significantly alter the results for any outcome, including body weight, waist circumference, body fat percentage, fasting glucose, fasting insulin, triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, high- density lipoprotein (HDL) cholesterol, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), energy intake or sugars intake. Excluding this trial also did not significantly affect heterogeneity (i.e. did not push the value for I2 across the threshold for serious inconsistency of 50%), although results for BMI became statistically significant (see section 3.1.1). The study was therefore retained in the main analyses.

This review includes 64 prospective cohort studies conducted in adults (representing approximately 35 unique cohorts), 15 cohort studies in children (representing 13 unique cohorts), one cohort study in children and adults (representing one unique cohort) and 17 cohort studies in

9 3. Results

pregnant women (representing 12 unique cohorts). Of the studies in adults, 47 were of mixed sex, 15 were exclusively female, and two were exclusively male. All studies of children were of mixed sex, except one that was exclusively girls. Follow-up in cohort studies in adults ranged from 2 years to more than 30 years, in children from 8 months to 10 years, and in pregnant women from 8 months to 16 years. Cohort studies in adults were conducted in Australia (n = 3), France (n = 4), Japan (n = 1), Mexico (n = 1), the Russian Federation (n = 1), Spain (n = 4), the United Kingdom (n = 1), the United States (n = 44) and multiple countries (n = 5). Cohort studies in children were conducted in Australia (n = 1), Denmark (n = 1), the United Kingdom (n = 1) and the United States (n = 12). The cohort study conducted in children and adults was conducted in Australia. Cohort studies in pregnant women were conducted in Canada (n = 1), Denmark (n = 6), Germany (n = 1), Iceland (n = 1), the Netherlands (n = 1), Norway (n = 2), Slovenia (n = 1), the United Kingdom (n = 1) and the United States (n = 3). Additional detail about the prospective cohort studies can be found in Table A3.2 in Annex 3. The prospective cohort studies included in this review adjusted extensively for potential confounders, which are summarized in Annex 5.

This review includes 41 case–control studies assessing cancer outcomes in adults (one study reports results from two populations separately, and one reports on multiple, unspecified populations together, for a total of 42 data sets). All case–control studies were conducted in populations of mixed weight. Two were conducted exclusively in males, three exclusively in females and the rest in mixed-sex populations. Twenty-two studies assessed effects of unspecified sweeteners, 11 of multiple sweeteners, seven of saccharin and two of aspartame. Studies were conducted in Argentina (n = 2), Canada (n = 4), China (n = 2), Denmark (n = 3), Egypt (n = 1), France (n = 2), Italy (n = 2), Japan (n = 2), Lebanon (n = 1), Serbia (n = 1), Spain (n = 1), Sweden (n = 2), the United Kingdom (n = 2), the United States (n = 15) and multiple countries (n =1). Two studies conducted in the United States assessing cancer in children were also included.1 Additional detail about the case–control studies can be found in Annex 3.

Results from nonrandomized controlled trials and cross-sectional studies are provided in sections 3.1, 3.2 and 3.3 as supplementary evidence when little to no evidence is available from trials, prospective cohort studies or case–control studies (in the case of cancer).

Risk of bias and GRADE assessments can be found in Annex 6 and Annex 7, respectively. Results of funnel plot analysis can be found in Annex 8.

3.1 Adults 3.1.1 Adiposity

A total of 32 RCTs (22, 23, 25–54) and 13 prospective cohort studies (55–69) reporting on measures of adiposity were included in meta-analyses. Results for measures of adiposity are summarized in Table 2.

As assessed in RCTs, higher intakes of NSS resulted in a reduction in body weight of 0.71 kg (Fig. 3) and BMI of 0.14 kg/m2, although the latter was not quite statistically significant (Fig. 4). No significant effects were observed for other measures of adiposity as assessed in RCTs (Table 2; Annex 9: Fig. A9.1–A9.5). Higher intakes of NSS were associated with a 0.14 kg/m2 increase in BMI and a 76% increase in risk of incident obesity as assessed in prospective cohort studies (Fig. 5 and 6). No other significant associations were observed in prospective cohort studies (Table 2; Annex 9: Fig. A9.6–A9.9).

Data from studies that could not be included in meta-analyses

Six RCTs reported no significant effect on weight or intermediate markers of adiposity in adults, but could not be included in the meta-analyses because of missing data (33, 70–75). In an RCT of

1 In addition, three case-control studies assessing outcomes other than cancer in adults were included in the review but were not assessed as part of the evidence base as data was available from higher quality RCTs and/or prospective observational studies.

10 Health effects of the use of non-sugar sweeteners

160

Fig. 2. Outcomes reported by study design and population

Adullts-–Rrandomiized conttrrollledttrriiall ((ongoiing)) A Ad du ullt ts s -–Rra an nd do om miiz ze ed d c co on nttrro ol l l le ed d ttrri ia al l
A Ad du ullt ts s -–Ccrro oss ss--sse ecctti io on na al l ssttu ud dy y

Adullts-–Cconttrrollledttrriiall((onggoiningg)) Adullts-–Cconttrrollledttrriiall
Adullts-–Ccohorrttssttudy Adullts-–Ccasse–cconttrrollssttuuddyy Chiilldren-–Rrandomiized conttrrollledttrriiall ((ongoiing)) Chiilldren-–Rrandomiized conttrrollledttrriiall Chiilldren-–Ccrrosss--sseccttiionallssttuuddyy Chiilldren-–Cconttrrollledttrriiall Chiilldren-–Ccohorrttssttuuddyy Chiilldren-–Ccasse–cconttrrollssttuuddyy

Miixed -–Rrandomiized conttrrollledttrriiall Miixed-–Ccrrosss--sseccttiionallssttuuddyy Miixed-–Ccohorrttssttuuddyy
P P r r e e g g n n a a n n t t w w o o m m e e n n - – C c r r o o s s s s - - s s e e c c t t i oi o n n a a l l s s t t u u d d y y Pregnant women-–Ccohorrttssttudy Pregnant women-–Ccaassee––cconttrrollssttuuddyy

140

120

100

Adullts-–Ccohorrttssttudy Adullts-–Ccasse–cconttrrollssttuuddyy Chiilldren-–Rrandomiized conttrrollledttrriiall ((ongoiing)) Chiilldren-–Rrandomiized conttrrollledttrriiall Chiilldren-–Ccrrosss--sseccttiionallssttuuddyy Chiilldren-–Cconttrrollledttrriiall Chiilldren-–Ccohorrttssttuuddyy Chiilldren-–Ccasse–cconttrrollssttuuddyy
Miixed -–Rrandomiized conttrrollledttrriiall Miixed-–Ccrrosss--sseccttiionallssttuuddyy Miixed-–Ccohorrttssttuuddyy

40 Pregnant women - Cross-sectional study Pregnant women – cross-sectional study

Pregnant women-–Ccohorrttssttudy Pregnant women-–Ccaassee––cconttrrollssttuuddyy

Number of studies

CVD: cardiovascular disease.
Note: Disease outcomes include both disease incidence and risk factors.

Table 2. Summary of results for NSS intake and measures of adiposity in adults

Measure of adiposity (unit)	No. of studies/cohorts	Effect estimate (95% CI)	I2 (%)	Figure
Weight (kg)	29 RCTs 4 cohorts (cont) 5 cohorts (hvl)	MD –0.71 (–1.13, –0.28) MD –0.12 (–0.40, 0.15) MD –0.01 (–0.67, 0.64)	83 76 49	3 A9.6 A9.7
BMI (kg/m2)	23 RCTs 5 cohorts (hvl)	MD –0.14 (–0.30, 0.02) MD 0.14 (0.03, 0.25)	71 79	4 5
Incident obesity	2 cohorts (hvl)	HR 1.76 (1.25, 2.49)	0	6
Waist circumference (cm)	10 RCTs 3 cohorts (hvl)	MD –0.24 (–1.06, 0.58) MD 0.92 (–1.73, 3.56)	74 85	A9.1 A9.8
Abdominal obesity	4 cohorts (hvl)	HR 1.33 (0.91, 1.96)	91	A9.9
Waist-to-hip ratio	3 RCTs	MD 0.00 (–0.01, 0.01)	0	A9.2
Body fat mass (kg)	6 RCTs	MD –0.54 (–1.56, 0.49)	87	A9.3
Body fat mass (%)	10 RCTs	MD –0.11 (–0.78, 0.56)	74	A9.4
Body lean mass (kg)	6 RCTs	MD –0.29 (–0.70, 0.11)	48	A9.5

cont: continuous, per serving; hvl: highest versus lowest category of intake. Note: Bold font indicates a statistically significant effect.

11 3. Results

Fig. 3. Effect of NSS intake on body weight (kg) in randomized controlled trials

both adults and children (76), overweight participants (n = 57) between 10 and 21 years of age (mean age: 19 years) were given capsules totalling 2.7 g aspartame daily or a lactose placebo. At the end of the intervention, when compared to the placebo arm, the aspartame arm had lost 1.09 kg (standard error [SE]: 0.87).

In a prospective cohort study conducted in both adults and children (14–22 years of age), substituting 100 g/day of SSBs with diet drink was association with a 0.20 kg (SE 0.05) higher BMI and a 0.18 cm (SE 0.05) higher waist circumference (77). In other prospective cohort studies, authors reported that intake of NSS-sweetened beverages is likely to represent an important driver of the relationship between lower education and greater weight gain over time in Australian women (78). No associations were observed between consumption of NSS-sweetened beverages and risk of weight gain (79), or the amount of fat in the liver or incidence of non-alcoholic fatty liver disease (80).

Subgroup and sensitivity analyses

Subgroup analyses suggest that the effect of NSS on body weight may be greatest in those who are overweight (Fig. 7), and those intentionally trying to lose weight by restricting energy intake (Fig. 8), though neither test for subgroup differences were statistically significant, and pooled effects for some of the subgroups may have been skewed by outliers. Differences were observed for individual subgroups in subgroup analysis of body weight and BMI by comparator: adding NSS to the diet compared with nothing (or placebo), and adding NSS to the diet compared with sugars (either NSS replacing sugars, or both NSS and sugars being added to the diet, in separate arms of a trial) both resulted in decreases in body weight and BMI, whereas NSS compared with water showed no effect on body weight and a nonsignificant increase in BMI (test for subgroup

12 Health effects of the use of non-sugar sweeteners

Fig. 4.

Effect of NSS intake on body mass index (kg/m2) in randomized controlled trials

Fig. 5.

Association between NSS intake and body mass index (kg/m2) in prospective cohort studies

Fig. 6.

Association between NSS intake and incident obesity in prospective cohort studies

13 3. Results

Fig. 7. Effect of NSS intake on body weight (kg) in randomized controlled trials, subgrouped by baseline weight status

differences was only statistically significant for BMI) (Fig. 9 and 10). The observed changes in body weight and BMI were likely mediated by a reduction in energy intake as all studies that compared NSS to sugars and reported both body weight or BMI, and energy intake collectively, showed reductions in body weight, BMI and energy intake (data not shown), whereas studies not comparing NSS to sugars did not collectively show a reduction in energy intake (section 3.1.7.1: Fig. 29). When studies were limited to those that gave explicit instructions to habitual consumers of SSBs or sugar-containing foods to replace these foods and beverages with alternatives sweetened with NSS, the effect on body weight remained but was slightly attenuated and became statistically nonsignificant (Fig. 11), and an effect on BMI was no longer observed (Fig. 12).

Sensitivity analyses in which one study that appeared to contain numerical errors and/or unusual results for some outcomes (25) was excluded did not significantly change the results for body

14 Health effects of the use of non-sugar sweeteners

Fig. 8. Effect of NSS intake on body weight (kg) in randomized controlled trials, subgrouped by study design (weight loss studies vs non–weight loss studies)

Note: Weight loss studies were those in which participants were instructed to restrict energy intake AND consume NSS or control. Weight maintenance studies were those that followed up participants after active weight loss, with instructions on energy intake designed to prevent weight gain. Non–weight loss studies were those that had no intentional weight loss component.

weight (mean difference [MD] –0.78; 95% confidence interval [CI] –1.20, –0.35; I2 83%) or BMI (MD –0.17; 95% CI –0.33, –0.02; I2 69%), although the result for BMI became statistically significant.

Greater weight reduction in trials of longer duration was suggested by subgroup analysis and meta-regression; however, results were not statistically significant for either (Annex 9: Fig. A9.10 and A9.11). Significant differences were also observed for subgroup analysis of BMI by consumption pattern; however, the differences between consumption pattern subgroups did not allow a coherent interpretation (Annex 9: Fig. A9.12). Results of meta-regression found a dose– response relationship between changes in body weight or BMI and changes in energy intake – that is, greater decreases in energy intake were associated with greater decreases in body weight and BMI (Annex 9: Fig. A9.13 and A9.14). Results of other subgroup analyses did not suggest meaningful differences (Annex 9: Fig. A9.15–A9.21).

15 3. Results

Fig. 9. Effect of NSS intake on body weight (kg) in randomized controlled trials, subgrouped by comparator

Note: Some studies appear more than once because they had multiple arms (e.g. comparing artificially sweetened beverages with both sugar-sweetened beverages and water, or separately comparing multiple different NSS with a control); therefore, the overall pooled effect is also slightly different from the main effect, and only effects for individual subgroups should be considered.

16 Health effects of the use of non-sugar sweeteners

Fig. 10. Effect of NSS on body mass index (kg/m2) in randomized controlled trials, subgrouped by comparator

17 3. Results

Fig. 11. Effect of NSS intake on body weight (kg) for trials with explicit replacement of sugars with NSS

Fig. 12. Effect of NSS intake on body mass index (kg/m2) for trials with explicit replacement of sugars with NSS

Sensitivity analyses using a fixed effects model, removing abstract-only publications, and removing crossover studies and studies of shorter duration (<8 weeks) did not significantly change the effect observed for body weight (data not shown). Sensitivity analysis in which studies that were at least partially funded by industry were removed attenuated the reduction in body weight, which was no longer statistically significant (MD –0.33 kg; 95% CI –0.80, 0.13; 18 studies with 1277 participants; I2 74%).

Supplementary results from nonrandomized controlled trials

In addition to the results observed for RCTs and prospective cohort studies, a reduction in body weight of 0.48 kg was observed in pooling of nonrandomized controlled trials (MD –0.48 kg; 95% CI –0.64, –0.32; 3 studies with 233 participants; I2 44%) (81-83) (Fig. A9.22).

3.1.2 Type 2 diabetes

Results for type 2 diabetes are summarized in Table 3. 3.1.2.1 Incident type 2 diabetes

Twelve prospective cohort studies (comprising 14 cohorts) reporting on the risk of developing type 2 diabetes were included in meta-analyses (66, 84–94). As assessed in prospective cohort studies, higher intakes of NSS were associated with increased risk of developing type 2 diabetes, regardless of whether the NSS were consumed in beverage form (a 23% increase in risk; Fig. 13) or added to foods or beverages by the consumer, i.e. tabletop (a 34% increase in risk; Fig. 14).1

1 Fagherazzi et al. (2013) (86) and Fagherazzi et al. (2017) (85) reported results for the entire French E3N cohort, which is part of the EPIC Interact European cohort. Interact Consortium et al. (2013) (94) includes a small number of the E3N cohort in its analysis (less than 1% of the full cohort). Therefore, both studies were included in the analysis of type 2 diabetes risk, with beverages as the exposure.

18 Health effects of the use of non-sugar sweeteners

To address reverse causation, all 12 prospective cohort studies adjusted for relevant confounders, including BMI (Annex 5), and most performed a number of relevant sensitivity analyses, including the exclusion of diabetes cases in the first 3–7 years of follow-up from baseline. Most studies reported quantitively or narratively that the effect was not significantly affected (Table 4).

Table 3. Summary of results for NSS intake and type 2 diabetes

Measure of type 2 diabetes (unit)

No. of studies/ cohorts

Effect estimate (95% CI)

I2 (%)

Figure

13 cohorts

HR 1.23 (1.14, 1.32)

2 cohorts

HR 1.34 (1.21, 1.48)

Incident type 2 diabetes (beverages)

Incident type 2 diabetes (tabletop)

Fasting glucose (mmol/L)

Fasting insulin (pmol/L)

HbA1c (%)

HOMA-IR

High fasting glucose

16 RCTs

10 RCTs

6 RCTs

11 RCTs

3 cohorts

MD –0.01 (–0.05, 0.04)

MD –0.49 (–4.99, 4.02)

MD 0.02 (–0.03, 0.07)

MD 0.03 (–0.32, 0.38)

HR 1.21 (1.01, 1.45)

14 0 A9.23

74 A9.24

0 A9.25

89 A9.26

47 A9.27

HbA1c: glycated haemoglobin; HOMA-IR: Homeostatic Model Assessment of Insulin Resistance. Note: Bold font indicates a statistically significant effect.

Fig. 13. Association between NSS-containing beverage intake and risk of type 2 diabetes in prospective cohort studies

Fig. 14. Association between tabletop NSS use and risk of type 2 diabetes in prospective cohort studies

19 3. Results

3.1.2.2

Intermediate markers of disease

Twenty-one RCTs (23, 25–30, 35–37, 39, 40, 45-47, 49, 51, 53, 95–97) and three prospective cohort studies (61, 62, 66) reporting on intermediate markers of type 2 diabetes were included in meta-analyses. No significant effects were observed for any measure of glycaemic control as assessed in RCTs (Table 3; Annex 9: Fig. A9.23–A9.26). Higher intakes of NSS were associated with a 21% increase in risk of high fasting glucose1 as assessed in prospective cohort studies (hazard ratio [HR] 1.21; 95% CI 1.01, 1.45; 3 studies with 11 213 participants; I2 47%) (Table 3; Annex 9: Fig. A9.27).

Because there was generally very little heterogeneity or very few studies for each outcome, subgroup analyses were not performed.

Table 4.

Summary of sensitivity analyses within cohort studies

Study

Key sensitivity analysis

Original effect (95% CI)

Post-sensitivity analysis (95% CI)

4-year lag in analysis (after change in beverage consumption)

1.02 (0.83, 1.25)

1.35 (1.04, 1.76)

4-year lag in analysis (after change in beverage consumption)

1.38 (0.98, 1.93)

Drouin-Chartier 2019 (NHS)

Drouin-Chartier 2019 (NHS II)

Drouin-Chartier 2019 (HPFS)

Fagherazzi 2013

Fagherazzi 2017

Gardener 2018

Hirahatake 2019

Huang 2017

InterAct Consortium 2013

Jensen 2020 Nettleton 2009 O’Connor 2015

Palmer 2008

Sakurai 2014

Excluding first 5 years

Excluding first 3 years

Excluding first 7 years

Excluding first 4 years

None reported

Excluding first 5 years

None reported

1.68 (1.19,

1.33 (1.20,

1.44 (0.93,

1.37 (0.98,

1.21 (1.08,

1.41 (0.70,

1.17 (0.93,

1.06 (0.83,

2.39)

1.47)

2.24)

1.92)

1.36)

2.80)

1.48)

1.36)

1.20 (1.12, 1.28) (all 3 cohorts pooled)

1.81 (1.19, 2.73)

1.76 (1.59, 1.96)

1.63 (1.04, 2.56)

No significant change

1.18 (1.02. 1.37)

Results not reported for NSS-sweetened beverages

NA
No significant change

1.03 (0.88,1.22)

NA
No significant change

Excluding first 2 and 5 years

1.13 (0.85, 1.52)

Adjusted for change in body weight

1.38 (1.04, 1.82)

Excluded those receiving dietary intervention for NCDs

1.71 (1.11, 2.63)

HPFS: Health Professionals Follow-up Study; NA: not applicable; NCDs: noncommunicable diseases; NHS: Nurses’ Health Study.

Results from studies that could not be included in meta-analyses

Eight trials that could not be included in the meta-analyses reported no significant effect of NSS on intermediate markers of diabetes (27, 31, 33, 52, 70, 72–74, 98). One study reported that NSS augmented glucose absorption (15%; P ≤ 0.05) and glycaemic responses to enteral glucose (26%; P ≤ 0.01) (99). Studies reporting on glucose and insulin area under the curve (AUC) and

1 High fasting glucose (as part of the criteria for assessing metabolic syndrome, as indicated in the relevant included studies) was defined as ≥100 mg/dL.

20 Health effects of the use of non-sugar sweeteners

incremental AUC (iAUC) were not amenable to meta-analysis; however, most did not report significant differences (23, 26, 31, 35, 53, 100, 101). One trial found a significant increase in glucose iAUC in the NSS arm compared with the sucrose arm (P < 0.05) (96).

In an RCT conducted in overweight participants, adults and children (n = 57) between 10 and 21 years of age (mean age 19 years) were given capsules or a lactose placebo. At the end of the intervention, fasting glucose was 0.32 mmol/L (SE 0.16) higher in the aspartame arm compared with the placebo arm (76).

3.1.3 All-cause mortality

Seven prospective cohort studies (comprising eight cohorts) reporting on the risk of all-cause mortality were included in meta-analyses (69, 102–107). As assessed in prospective cohort studies, higher intakes of NSS-containing beverages were associated with a 12% increase in risk of all-cause mortality (Fig. 15). Three of the six cohorts with Ptrend data had Ptrend values <0.5. In addition, three of the studies with positive associations that conducted sensitivity analyses, in which cases were excluded from the first 3–8 years of follow-up, reported little to no impact on results. In the 2019 study by Malik et al. (102), the effect in the Nurses’ Health Study (NHS) cohort was attenuated when the data were adjusted for incident hypertension, hypercholesterolaemia, type 2 diabetes, coronary heart disease and stroke, but was still significant in those consuming four or more NSS-sweetened beverages per day. The association observed in the 2020 study by Anderson et al. (69) was no longer statistically significant when participants with recent weight loss or who died in the first 2 years of follow-up were excluded. The association was stronger when participants with prevalent disease associated with unintentional weight loss at baseline were excluded from the analysis or when BMI was not adjusted for in the multivariate model.

Fig. 15. Association between NSS-containing beverage intake and risk of all-cause mortality in prospective cohort studies

3.1.4 Cardiovascular diseases

Results for cardiovascular diseases are summarized in Table 5. 3.1.4.1 Cardiovascular disease mortality

Four prospective cohort studies (comprising five cohorts) reporting on the risk of cardiovascular disease mortality were included in meta-analyses (102, 104, 108, 109). As assessed in prospective cohort studies, higher intakes of NSS-containing beverages were associated with a 19% increase in risk of cardiovascular disease mortality (Fig. 16).

21 3. Results

Fig. 16. Association between NSS-containing beverage intake and risk of cardiovascular disease mortality in prospective cohort studies

3.1.4.2 Cardiovascular events

Three prospective cohort studies reporting on the risk of cardiovascular events were included in meta-analyses (108–110). As assessed in prospective cohort studies, higher intakes of NSS- containing beverages were associated with a 32% increase in risk of cardiovascular events1 (Fig. 17).

Fig. 17. Association between NSS-containing beverage intake and risk of cardiovascular events in prospective cohort studies

3.1.4.3 Coronary heart disease

Four prospective cohort studies reporting on the risk of coronary heart disease were included in this review (103, 108, 111, 112). As assessed in prospective cohort studies, higher intakes of NSS- containing beverages were associated with a nonsignificant increase in risk of coronary heart disease (Fig. 18). A fifth prospective cohort study found no association between NSS-containing beverage intake and coronary heart disease mortality (HR 1.11; 95% CI 0.72, 1.70) (107).

Fig. 18. Association between NSS-containing beverage intake and risk of coronary heart disease in prospective cohort studies

1 Cardiovascular events in Gardener et al. (2012) (108) included stroke, myocardial infarction and vascular death. In Vyas et al. (2015) (109), they included coronary heart disease, myocardial infarction, heart failure, coronary revascularization procedure, ischaemic stroke, peripheral artery disease and cardiovascular disease mortality.

22 Health effects of the use of non-sugar sweeteners

3.1.4.4 Stroke

Five prospective cohort studies (comprising six cohorts) reporting on the risk of stroke were included in this review (103, 104, 108, 113, 114). As assessed in prospective cohort studies, higher intakes of NSS-containing beverages were associated with a 19% increase in risk of any type of stroke (Fig. 19), with significant increases in risk of both haemorrhagic stroke (HR 1.33; 95% CI 1.03, 1.72; two studies and three comparisons with 196 884 participants; I2 22%) and ischaemic stroke (HR 1.22; 95% CI 1.04, 1.44; three studies and four comparisons with 200 827 participants; I2 44%) when assessed individually (Annex 9: Fig. A9.28 and A9.29). Sensitivity analyses conducted within the individual studies, in which those with significant weight change within 4–5 years of baseline (113), or type 2 diabetes or cardiovascular disease within 3 years of baseline were removed (103), did not significantly affect the results. However, removing those with prevalent hypertension, cardiovascular disease or type 2 diabetes abrogated the effect in the 2017 study by Pase et al. (114).

Fig. 19. Association between NSS-containing beverage intake and risk of stroke in prospective cohort studies

3.1.4.5 Hypertension

Four prospective cohort studies (comprising six cohorts) reporting on the risk of hypertension1 were included in this review (61, 62, 66, 115). As assessed in prospective cohort studies, higher intakes of NSS-containing beverages were associated with a 13% increase in risk of hypertension (Fig. 20).

Fig. 20. Association between NSS-containing beverage intake and risk of hypertension in prospective cohort studies

1 Defined as systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg, or taking antihypertensive medication.

23 3. Results

3.1.4.6 Intermediate markers of disease

Nineteen RCTs (23, 25, 27–30, 36-40, 46–50, 52, 96, 97) and four prospective cohort studies (61, 62, 66, 116) reporting on intermediate markers of cardiovascular diseases were included in meta- analyses. As assessed in RCTs, higher intakes of NSS did not have a significant effect on systolic or diastolic blood pressure (Fig. 21 and 22), though a trend to lower systolic blood pressure was observed with NSS intake. With the exception of a small, but significant, increase in total cholesterol:HDL cholesterol (MD 0.09; 95% CI 0.02, 0.16; four trials with 326 participants; I2 0%) (Annex 9: Fig. A9.30), no significant effects were observed for any blood lipid measure in RCTs or prospective cohort studies (Table 5; Annex 9: Fig. A9.31–A9.34), including LDL cholesterol or triglycerides (Fig. 23 and 24).

Fig. 21. Effect of NSS intake on systolic blood pressure (mmHg) in randomized controlled trials

Fig. 22. Effect of NSS intake on diastolic blood pressure (mmHg) in randomized controlled trials

24 Health effects of the use of non-sugar sweeteners

Fig. 23. Effect of NSS intake on LDL cholesterol (mmol/L) in randomized controlled trials

Fig. 24. Effect of NSS intake on triglycerides (mmol/L) in randomized controlled trials

25 3. Results

Table 5. Summary of results for NSS intake and cardiovascular diseases

Measure of CVD (unit)

Number of studies/cohorts

Effect estimate (95% CI)

I2 (%)

Figure

CVD mortality

Cardiovascular events

Coronary heart disease

Stroke

Hypertension

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

Total cholesterol (mmol/L)

LDL cholesterol (mmol/L)

HDL cholesterol (mmol/L)

Total cholesterol:HDL cholesterol

Low HDL cholesterol

Triglycerides (mmol/L)

High triglycerides

5 cohorts

3 cohorts

4 cohorts

6 cohorts

14 RCTs

13 RCTs

14 RCTs

12 RCTs

13 RCTs

4 RCTs

4 cohorts

14 RCTs

4 cohorts

HR 1.19 (1.07, 1.32)

HR 1.32 (1.17, 1.50)

HR 1.16 (0.97, 1.39)

HR 1.19 (1.09, 1.29)

HR 1.13 (1.09, 1.17)

MD –1.33 (–2.71, 0.06)

MD –0.51 (–1.68, 0.65)

MD 0.01 (–0.09, 0.11)

MD 0.03 (–0.03, 0.09)

MD 0.00 (–0.03, 0.03)

MD 0.09 (0.02, 0.16)

HR 1.03 (0.92, 1.16)

MD –0.04 (–0.11, 0.04)

HR 1.03 (0.88, 1.21)

25 16

0 17

75 18

0 19

48 20

38 21

40 22

32 A9.31

32 23

45 A9.32

0 A9.30

0 A9.33

55 24

37 A9.34

CVD: cardiovascular diseases; HDL: high-density lipoprotein; LDL: low-density lipoprotein. Note: Bold font indicates a statistically significant effect.

Data from studies that could not be included in meta-analyses

Five RCTs that could not be included in meta-analyses reported no effect of NSS on intermediate cardiovascular disease markers (31, 33, 70, 72–74). One prospective cohort study found no association between NSS-sweetened beverage intake and common carotid artery intima-media thickness (CCA-IMT) (P = 0.96), common carotid artery adventitial diameter (CCA-AD) (P = 0.34) or carotid plaque (P = 0.39) (117).

In a replacement analysis from the Harvard Pooling Project of Diet and Coronary Disease1 that could not be included in the meta-analysis, replacing SSBs with beverages containing NSS was associated with a 12% reduction in risk of coronary events (HR 0.88; 95% CI 0.81, 0.95; 305 480 participants); however, this study did not allow independent assessment of NSS-sweetened beverages (118).

In an RCT conducted in overweight adults and children (n = 57) between 10 and 21 years of age (mean age: 19 years), participants were given capsules or a lactose placebo. At the end of the intervention, the aspartame arm compared with the placebo arm had an increase of 1 mmHg (SE 3.5) in systolic blood pressure, 1 mmHg (SE 2.6) in diastolic blood pressure, 0.18 mmol/L (SE 0.23) in total cholesterol, and 0.12 mmol/L (SE 0.10) in triglycerides (76).

3.1.5 Cancer

Results for cancer are summarized in Table 6.

1 Data were pooled from the following cohorts and studies: Atherosclerosis Risk in Communities Study, Alpha-Tocopherol and Beta-Carotene Cancer Prevention Study, Health Professionals Follow-up Study, Iowa Women’s Health Study, Women’s Health Study and Nurses’ Health Study.

26 Health effects of the use of non-sugar sweeteners

3.1.5.1 Cancer mortality

Three prospective cohort studies (comprising four cohorts) reporting on the risk of cancer mortality were included in meta-analyses (102, 104, 107). As assessed in prospective cohort studies, no significant association was observed between higher intakes of NSS-containing beverages and cancer mortality (Fig. 25).

Fig. 25. Association between NSS-containing beverage intake and risk of cancer mortality in prospective cohort studies

3.1.5.2 Cancer incidence

A total of 48 studies investigating the association between NSS and cancer were included in meta-analyses: 39 case–control studies (119–162) and nine cohort studies (163–171).

As assessed in prospective cohort studies, no significant association was observed between higher intakes of primarily NSS-containing beverages and any type of cancer (Fig. 26).

Fig. 26. Association between primarily NSS-containing beverage intake and risk of any type of cancer in prospective cohort studies

942600

Note: In calculating the total number of participants across all studies, the values displayed for NIH-AARP, MCCS, NHS and HPFS in separate studies were averaged, to avoid double-counting participants.

27 3. Results

Table 6. Summary of results for NSS intake and cancer

Cancer site

No. of studies/cohorts

Effect estimate (95% CI)

I2 (%)

Figure

Cancer mortality

Any type

Bladder Brain

Breast

Colorectum

Endometrium

Kidney Larynx

Lung

Oesophagus

Oral cavity and pharynx Ovary

Pancreas

Prostate

Stomach Leukaemia

Multiple myeloma

Hodgkin lymphoma

Non-Hodgkin lymphoma
All cancers
Cancers not related to obesity

Cancers related to obesitya

4 cohorts

7 cohorts

26 case–controls

HR 1.02 (0.92, 1.13)

HR 1.02 (0.95, 1.09)

OR 1.31 (1.06, 1.62)

50 25

37 26

92 27

A9.37 NA

A9.38 A9.39

A9.40 A9.41

NA NA

A9.42 NA

NA NA

0 A9.43

NA NA

A9.44 A9.45

A9.46 A9.47

A9.48 NA

0 A9.49

70 A9.50

NA NA

64 A9.51

NA NA

2 case–controls 1 cohort	OR 1.13 (0.76, 1.69) RR 0.73 (0.46, 1.15)	0 NA
3 case–controls 4 cohorts	OR 0.83 (0.64, 1.08) HR 0.98 (0.89, 1.09)	47 55
3 case–controls 3 cohorts	OR 0.85 (0.68, 1.07) HR 0.80 (0.63, 1.01)	0 0
1 case–control 1 cohort	OR 0.96 (0.66, 1.39) HR 0.81 (0.42, 1.56)	NA NA
4 case–controls 1 cohort	OR 1.25 (0.94, 1.65) HR 0.92 (0.46, 1.84)	61 NA

1 case–control

2 case–controls

1 case–control

OR 2.34 (1.20, 4.56)

OR 0.40 (0.26, 0.61)

OR 1.24 (0.54, 2.83)

OR 0.77 (0.36, 1.64)

1 case–control 1 cohort	OR 0.56 (0.38, 0.82) HR 1.37 (0.72, 2.61)	NA NA
4 case–controls 3 cohort	OR 0.88 (0.51, 1.50) RR 1.06 (0.88, 1.28)	83 0
2 case–controls 2 cohorts	OR 0.88 (0.30, 2.62) HR 1.09 (0.67, 1.75)	40 66
2 case–controls 1 cohort	OR 0.79 (0.50, 1.26) HR 1.03 (0.53, 1.99)	0 NA

3 cohorts

4 cohorts

1 cohort

4 cohorts

1 cohort

RR 1.24 (0.92, 1.69)

RR 1.05 (0.70, 1.59)

RR 0.77 (0.44, 1.33)

RR 1.08 (0.87, 1.34)

HR: 1.23 (1.02, 1.48)

HR: 1.00 (0.79, 1,27)

1 case–control 1 cohort

RR: 0.90 (0.67, 1.23) HR : 1.00 (0.84, 1.19)

NA NA

NA: not applicable.
a Defined as liver cancer, aggressive prostate cancer, ovarian cancer, gallbladder cancer, kidney cancer, colorectal cancer,

oesophageal cancer, postmenopausal breast cancer, pancreatic cancer, endometrial cancer and gastric cardia cancer

(165).
Note: Bold font indicates a statistically significant effect.

28 Health effects of the use of non-sugar sweeteners

Meta-analysis results of the association between NSS intake and individual types of cancers are summarized in Table 6. As assessed in case–control studies, a 31% increase in risk of bladder cancer was observed with NSS intake (Fig. 27). Subgroup analysis suggests that tabletop use of NSS, particularly saccharin, may be associated with bladder cancer (Annex 9: Fig. A9.35 and A9.36), although the differences between subgroups were not statistically significant for saccharin. Other significant associations were observed for NSS intake and increased risk of cancer of the larynx and cancers not related to obesity,1 and decreased risk of cancer of the lung and ovary; however, only one or two studies contributed data to each of these results, so they must be interpreted with caution. All other results were nonsignificant, including a study of the effects of consumption of NSS-sweetened beverages on survival in women already diagnosed with breast cancer (not shown in Table 6) (106), though a trend towards decreased risk of colorectal cancer with NSS use was observed.

Fig. 27. Association between NSS intake and risk of bladder cancer

3.1.6 Chronic kidney disease

Results for chronic kidney disease are summarized in Table 7.
Two RCTs (29, 97) and two prospective cohort studies (173, 174) reporting on the risk of chronic

kidney disease were included in meta-analyses.
As assessed in prospective cohort studies, no association was observed between NSS intake and

chronic kidney disease2 (Annex 9: Fig. A9.52). One prospective study reported an association

1 Defined as prostate cancer, diffuse large B-cell lymphoma, noncardia gastric cancer, lung cancer, melanoma, premenopausal breast cancer, bladder cancer, brain cancer, cancer of unknown primary, lymphoid leukaemia and other cancers (172)
2 Lin 2011 reported the association between NSS use and decline in estimated glomerular filtration rate (eGFR) of ≥30% (173), and Rebholz 2017 the association between NSS use and chronic kidney disease with one defining characteristic being a ≥25% decline in eGFR (174).

29 3. Results

Table 7. Summary of results for NSS intake and chronic kidney disease

Measure of chronic kidney disease

No. of trials/cohorts

Estimate (95% CI)

I2 (%)

Figure

Chronic kidney disease

Incident end-stage renal disease

Microalbuminuria

Creatinine (mmol/L)

Albumin (g/L)

NA: not applicable.

2 cohort

1 cohort

2 RCTs

HR 1.41 (0.89, 2.24)

OR 1.64 (1.18, 2.28)

OR 0.92 (0.52, 1.64)

MD 8.80 (–14.65, 32.25)

MD 0.00 (–0.56, 0.56)

86 A9.52

NA NA

92 A9.53

0 A9.54

between NSS intake and a 64% increase in risk of end-stage renal disease (95% CI 1.18, 2.28; one study with 15 368 participants). No other significant effects or associations were observed.

3.1.7 Eating behaviour

Twenty-six RCTs (22, 23, 25–31, 34–37, 39, 41–45, 47, 50, 52–54, 175, 176) were included in meta- analyses.

3.1.7.1 Energy intake

As assessed in RCTs, higher intakes of NSS resulted in a reduction in total energy intake of more than 560 kJ per day (Fig. 28). Subgroup analysis indicates that energy intake is reduced when NSS are used to replace sugars (Fig. 29), but also in mixed-weight or overweight/obese individuals (Fig. 30), although the difference between subgroups in the latter is not statistically significant and there is considerable residual heterogeneity within most individual subgroups. Results of additional subgroup analyses can be found in Annex 9: Fig. A9.55–A9.58.

Fig. 28. Effect of NSS intake on total energy intake (kJ/day) in randomized controlled trials

30 Health effects of the use of non-sugar sweeteners

Fig. 29. Effect of NSS intake on total energy intake (kJ/day) in randomized controlled trials, subgrouped by comparator

Note: Some studies appear more than once because they had multiple arms (e.g. comparing artificially sweetened beverages with both sugar-sweetened beverages and water, or separately comparing multiple different NSS to a control); therefore, the overall pooled effect is also slightly different from the main effect, and only effects for individual subgroups should be considered.

In a nonrandomized controlled trial that compared responses to NSS-sweetened beverages, SSBs and water in habitually high and low consumers of NSS-sweetened beverages, high consumers had a greater energy intake than low consumers (177).

3.1.7.2 Hunger

As assessed in RCTs, no significant effect of NSS intake on subjective measures of hunger was observed (standardized mean difference [SMD] 0.24; 95% CI –0.86, 0.38; five trials with 817 participants; I2 100%) (Annex 9: Fig. A9.59). In addition, in one trial, the participants in the control arm reported overall higher hunger scores compared with an arm receiving stevia (52). Three other RCTs (41–43) and one nonrandomized controlled trial (177) reported no effects narratively.

31 3. Results

3.1.7.3 Satiety

As assessed in RCTs, a small but significant decrease in subjective measures of satiety or fullness was observed with NSS intake (SMD –0.15; 95% CI –0.30,–0.01; three trials with 518 participants; I2 98%) (Annex 9: Fig. A9.60). In addition, one RCT (41) and one nonrandomized controlled trial (177) reported no effects narratively.
3.1.7.4 Appetite and desire to eat

As assessed in RCTs, a small but significant effect of NSS intake on subjective measures of appetite or desire to eat was observed (SMD 0.23; 95% CI 0.04, 0.42; three trials with 518 participants; I2 99%) (Annex 9: Fig. A9.61). Two additional RCTs reported no effects narratively (32, 41).

In a nonrandomized controlled trial that compared responses to NSS-sweetened beverages, SSBs and water in habitually high and low consumers of NSS-sweetened beverages, high consumers had a greater desire to eat than low consumers, independent of beverage (177).

Fig. 30. Effect of NSS intake on total energy intake (kJ/day) in randomized controlled trials subgrouped by body weight status

32 Health effects of the use of non-sugar sweeteners

3.1.7.5 Other outcomes related to eating behaviour

One RCT found no effect of NSS, compared with no NSS, on eating control (22). Another found lower ingestive frequency and smaller portions in the NSS arm, but no difference in preoccupation with food (31). In a third trial comparing NSS and sugars, no differences in a three-factor eating questionnaire (rating attitudes about foods and body weight) were found between the two arms (41).

In an analysis of the cross-sectional National Health and Nutrition Examination Survey (NHANES) data, individuals who consumed NSS had more eating episodes per day, which started earlier in the morning and lasted longer across the day, than those who did not (178). Another cross- sectional study comparing heavy users and non-users of NSS-sweetened beverages found that heavy users scored higher on body weight concerns and guilt related to overeating (179).

3.1.8 Sweet preference

3.1.8.1 Sugars intake

Twelve RCTs were included in meta-analyses (22, 25–27, 37, 41–43, 45, 46, 175, 176, 180). As assessed in RCTs, higher intakes of NSS resulted in a reduction in sugars intake of approximately 39 g per day (Fig. 31). Not unexpectedly, subgroup analysis indicates that sugars intake is reduced significantly when NSS are used to replace sugars (Fig. 32), but also in overweight/obese individuals (Fig. 33), although there is considerable residual heterogeneity within the sugars and overweight/obese subgroups themselves. Results of additional subgroup analyses can be found in Annex 9: Fig. A9.62–A9.65.

Fig. 31. Effect of NSS intake on sugars intake (g/day) in randomized controlled trials

33 3. Results

Fig. 32. Effect of NSS intake on sugars intake (g/day) in randomized controlled trials, subgrouped by comparator

Fig. 33. Effect of NSS intake on sugars intake (g/day) in randomized controlled trials, subgrouped by body weight status

34 Health effects of the use of non-sugar sweeteners

Data from studies that could not be included in meta-analyses

Several studies reported on the effects of NSS intake on measures related to sweet taste perception, including sweet preference and liking, and sweet taste threshold. In two RCTs comparing sugars with NSS, desire for sweets changed over the course of the intervention but did not differ between arms (22, 41). In another trial comparing NSS-sweetened beverages with water, individuals who were given the NSS-sweetened beverage did not significantly choose more sweet foods during the test meal than those who were given water (175). A fourth trial, comparing NSS-sweetened, sugar-sweetened and unsweetened beverages, found that sweetness threshold was reduced in the unsweetened beverage arm, but not in the NSS-sweetened or sugar- sweetened beverage arms (28). A fifth trial reported that those who replaced SSBs with either NSS-sweetened beverages or water showed no differences in liking between beverages and that both were equally effective in reducing consumption of SSBs (181). A sixth trial reported a significant positive correlation between sweet cravings and sugars intake but not between sweet cravings and stevia intake (52).

In a nonrandomized controlled trial that compared responses to NSS-sweetened beverages, SSBs and water in habitually high and low consumers of NSS-sweetened beverages, low consumers demonstrated an increase in appetite in response to sweet taste that high consumers did not, suggesting a decoupling of expectation of energy with sweet taste in the high consumers (177).

In a cross-sectional analysis comparing high and low users of NSS-sweetened beverages and SSBs, high users preferred sweeter orange juice than low users (182).

3.1.9 Dental caries

In a 6-month RCT, participants were assigned to consume sugar-sweetened or NSS-sweetened soft drinks, and neither group developed caries nor experienced acid erosion of the enamel at any point during the intervention (183).

3.1.10 Mood

In two similar RCTs conducted in normal-weight (44) and overweight women (42), who were provided with aspartame-sweetened or sucrose-sweetened soft drinks for 4 weeks, no effect was found on mood. Similarly, in an RCT in which participants were provided aspartame-sweetened, sucrose-sweetened or unsweetened beverages and capsules for 20 days, no effect was found on mood (184).

A prospective cohort study found an association between consuming NSS-sweetened beverages and increased risk of depression over 7 years of follow-up in adults (adjusted odds ratio [OR] for soft drinks 1.25; 95% CI 1.15, 1.35; and adjusted OR for coffee or tea 1.11; 95% CI 0.99, 1.24) (185). However, two additional prospective cohort studies did not find a significant association between NSS intake and depression over 1–4 years of follow-up (186, 187), or with anxiety or general mood.

3.1.11 Neurocognition

In an RCT in which adults were given aspartame-sweetened, sucrose-sweetened or unsweetened beverages and supplements over 20 days, there were no significant effects on cognitive or neuropsychological measures (verbal learning, attention span, memory, motor response, cognitive efficiency, long-term memory) (184). In a second RCT, those receiving stevia for 6 weeks did not display any changes in cognitive function, whereas those receiving sucralose showed a significant decrease in overall memory, encoding memory and executive functions (54).

In a prospective cohort study, after 6 years of follow-up, adults drinking NSS-sweetened beverages more than once per month had nonsignificantly lower cognitive function (STICS-m1 score difference: b –0.19; 95% CI –0.78, 0.40; P = 0.53) (188). In another cohort study, the 10-year

1 Spanish version of the modified Telephone Interview for Cognitive Status (TICS-m)

35 3. Results

3.1.12

3.2 3.2.1

risk of developing dementia or Alzheimer’s disease was increased among adults consuming NSS- sweetened beverages daily compared with those consuming none (HR 2.47; 95% CI 1.15, 5.30, for dementia; and HR 2.89; 95% CI 1.18, 7.07, for Alzheimer’s disease), adjusted for prevalent hypertension, cardiovascular diseases, type 2 diabetes and risk factors for these diseases (114).

Behaviour

No studies in adults were identified.

Children

Adiposity

Results are summarized in Table 8.

Two RCTs (189, 190) and 14 cohort studies (191–204) reported on NSS intake and measures of adiposity in children.

Meta-analyses of the small number of studies reporting data in a manner amenable to meta- analysis yielded no significant results for any measure of adiposity. One fairly large, well- conducted RCT, however, reported significant reductions in body weight, BMI z-score (i.e. BMI adjusted for child age and sex), waist circumference and body fat mass when SSBs were replaced with NSS-sweetened beverages (189).

Table 8.

Summary of results for NSS intake and measures of adiposity in children

Adiposity outcomes (unit)

No. of studies

Effect estimate (95% CI)

MD –1.01 (–1.54, –0.48)

MD 0.03 (–0.14, 0.21)

I2 (%)

Figure

1 RCT
2 cohorts

NA 0

5 cohorts (cont) 2 cohorts (hvl)

MD 0.08 (–0.01, 0.17) MD 0.04 (–0.32, 0.40)

89 44

2 RCTs
3 cohorts (cont) 1 cohort (hvl)

MD –0.07 (–0.26, 0.11) MD –0.23 (–0.70, 0.25) MD 0.0 (–0.3, 0.3)

48 86 NA

Body weight BMI (kg/m2)

BMI z-score

Waist circumference (cm) Body fat mass (kg)

Body fat mass (%) Overweight

1 RCT

2 cohorts

MD –0.66 (–1.23, –0.09)

OR 1.25 (0.43, 3.66)

NA A9.66

A9.67 A9.68

A9.69 A9.70 NA

NA NA

NA A9.71

36 A9.72

1 RCT 1 cohort	MD –0.57 (–1.02, –0.12) MD –1.00 (–2.52, 0.52)	NA NA
1 RCT 2 cohorts	MD –1.07 (–1.99, –0.15) MD –1.53 (–5.73, 2.66)	NA 77

cont: continuous, per serving; hvl: highest versus lowest category of intake; NA: not applicable. Note: Bold font indicates a statistically significant effect.

3.2.2 Type 2 diabetes

No studies reported on development of type 2 diabetes in children, but one nonrandomized crossover trial (205) and one prospective cohort study (193) reported on intermediate markers. In a trial comparing sucrose, aspartame or saccharin given for 3 weeks to 3–10-year-old children, NSS collectively did not significantly affect postprandial glucose (MD 0.22 mmol/L; SE 0.29) when compared with sucrose. In a cohort of 12–18-year-old overweight children followed up for 1 year, chronic consumers of NSS-sweetened beverages had no difference in intermediate markers of diabetes when compared with NSS-sweetened beverage initiators and non-consumers, except for glycated haemoglobin (HbA1c), which increased more in chronic consumers of NSS-sweetened beverages (P = 0.01).

36 Health effects of the use of non-sugar sweeteners

3.2.3 Cardiovascular diseases

No studies reported on development of cardiovascular diseases in children, but one prospective cohort study (193) reported on intermediate markers. In a cohort of 12–18-year-old overweight children followed up for 1 year, chronic consumers of NSS-sweetened beverages had no difference in total cholesterol, HDL cholesterol, LDL cholesterol or triglycerides when compared with NSS- sweetened beverage initiators and non-consumers.
3.2.4 Cancer

Two case–control studies reported on NSS intake and brain cancer in children (206, 207). One study looked at mothers’ intake of NSS-sweetened beverages during pregnancy and cancer in offspring, and the other at intake of aspartame from drinks and tabletop sweeteners by both mothers during pregnancy and offspring in childhood. Intake of NSS was not significantly associated with brain cancer in offspring (OR 1.14; 95% CI 0.80, 1.63; two studies with 1151 participants; I2 5%) (Annex 9: Fig. A9.73).
3.2.5 Eating behaviour

3.2.5.1 Energy intake

Four studies of mixed design reported on NSS intake and daily energy intake (190, 193, 200, 205). Results varied considerably and are summarized in Table 9.

Table 9. Summary of results for energy intake in children

Study

Design

Comparison

MD in kJ/day (SE)

Taljaard 2013

Wolraich 1994
Davis 2018 Striegel-Moore 2006

RCT NSS vs sugar

Non-RCT NSS vs sugar

Cohort Per 100 g/day increase in diet soda

386 –419 (204)

48 –1066 (not reported) 2462 (572)

432 (661) 2371 122 (17)

Cohort

Chronic NSSB users vs never users Initiators of NSSB vs never users

84 89

kJ: kilojoules; MD: mean difference; n: number of study participants; NSSB: NSS-sweetened beverages; SE: standard error.

3.2.5.2 Hunger

One RCT conducted in children reported no effect of NSS on hunger in a narrative manner (205).
3.2.5.3 Satiety

In one RCT conducted in children comparing NSS-sweetened beverages and SSBs, subjective assessment of satiety was not significantly different (208). The same trial found that children liked and wanted the NSS-sweetened beverages slightly less than the SSBs after 18 months.

3.2.6 Sweet preference

3.2.6.1 Sugar intake

Three studies reported on NSS intake and sugars intake (193, 200, 205). In a nonrandomized controlled trial, the sugars intake of children given foods and drinks with NSS was 88 g/day less than for those given foods and drinks with sucrose. In a 1-year-long prospective cohort study, chronic users of NSS-sweetened beverages had a sugars intake that was 40.2 g/day (SE 11.6) higher than never users, whereas initiators of NSS-sweetened beverage use had a sugars intake that was 23.9 g/day (SE 17.9) lower than never users. In a 10-year-long prospective cohort study, for every 100 g/day increase in NSS-sweetened beverage intake, sugars intake tended to decrease, but not significantly. Results are summarized in Table 10.

37 3. Results

Table 10. Summary of results for sugars intake in children

Study

Design

Comparison

MD (SE)

Wolraich 1994 Davis 2018 (SOLAR)

Striegel-Moore 2006

Non-RCT

Cohort

NSS vs sugar

Per 100 g/day increase in diet soda

48 –88.3 (not reported)

40.2 (11.6) –23.9 (17.9)

2371 –0.3 (0.2)

Cohort

Chronic NSSB users vs never users Initiators of NSSB vs never users

84 89

MD: mean difference; n: number of study participants; NSSB: NSS-sweetened beverages; SE: standard error.

3.2.7 Dental caries

In one RCT, snacks containing stevia or sugars were given twice daily to children for 6 weeks. At the end of the trial, the concentrations of cariogenic Streptococcus mutans bacteria and lactobacilli (χ2 8.01; P < 0.01), and the probability of developing caries (measured by a cariogram) in the stevia arm had decreased compared with baseline, whereas there were no statistically significant changes in the sugars arm (209).

In another RCT, mouth rinse containing stevia or placebo was used daily by children for 6 months. At the end of the trial, there was a significant improvement in the stevia arm compared with the placebo arm in plaque scores (P = 0.03) and gingival scores (P = 0.01). There were no changes in the number of cavitated lesions in the stevia arm, but there was an increase in cavitated lesions in the placebo arm (from 5.6% to 5.8%) (210).

A prospective cohort study found that low intakes of NSS-sweetened beverages were associated with fewer teeth surfaces having caries compared with no intake (P < 0.025). However, the association with high intakes of NSS-sweetened beverages was not reported (211).

A cross-sectional study found that consumption of NSS-sweetened beverages (≥1 cup/day) was associated with higher OR of toothache (adjusted for age, sex, socioeconomic status, language background, place of residence and brushing teeth) (212). Another cross-sectional study found that NSS intake was higher in those with caries than in those without (P = 0.036), but did not find any significant difference in caries prevalence according to NSS-sweetened beverage intake (213).
3.2.8 Mood

A nonrandomized controlled trial in which children were given sucrose, aspartame or saccharin for 3 weeks in a crossover manner found no differences in mood (205). However, a cross-sectional study among children found that children who consumed NSS-sweetened foods or drinks had higher theta/beta ratios (an electroencephalographic measure used to assess attention, emotional regulation, or resilience to stress), which may indicate a negative impact on mood (214).
3.2.9 Behaviour

In a nonrandomized controlled trial, children who were described by their parents as sensitive to sugars were given sucrose, aspartame or saccharin for 3 weeks in a crossover manner. As rated by their parents and teachers, there were no significant differences between the diets in the ratings of different measures of the children’s behaviour, including conduct, attention deficit, deviation, attention, hyperactivity, social skills or oppositional behaviour (205).
3.2.10 Neurocognition

In an RCT, children were given drinks with sucralose or sucrose for 8.5 months. There were no significant differences between the two groups in cognition measures (tested using the Kaufman Assessment Battery for Children version II [KABC-II] subtests and the Hopkins Verbal Learning Test [HVLT]) (190).

38 Health effects of the use of non-sugar sweeteners

In a prospective cohort study following children in utero up to 7 years of age, early and mid- childhood cognition scores were inversely associated with maternal intake of NSS-sweetened beverages during pregnancy (PPVT-III,1 early childhood: –1.2; 95% CI –2.9, 0.5; total WRAVMA, early childhood: –1.5; 95% CI –2.9,–0.1; KBIT-II verbal, mid-childhood: –3.2; 95% CI –5.0, –1.5; KBIT-II nonverbal, mid-childhood: –2.0; 95% CI –4.3, 0.2; WRAVMA drawing, mid-childhood: –1.7; 95% CI –4.1, 0.6; WRAML visual memory, mid-childhood: –0.1; 95% CI –0.7, 0.5); however, there was no association between early and mid-childhood cognition scores and childhood intake of NSS-sweetened beverages at 3 years (215).

In a nonrandomized controlled trial in which children were given sucrose, aspartame or saccharin for 3 weeks in a crossover manner, no significant differences were found in cognition (205).

3.2.11 Asthma

A cross-sectional analysis within the PIAMA birth cohort found that intake of NSS-sweetened beverages in 11-year-old children (≥2 glasses/week) was associated with higher but nonsignificant odds of asthma (adjusted OR 1.08; 95% CI 0.74, 1.59) (216).
3.2.12 Allergies

No studies were identified that directly assessed allergies in children consuming NSS. See Section 3.3.3.4.

3.3 Pregnant women 3.3.1 Maternal outcomes

3.3.1.1 Gestational diabetes

In a cohort study among pregnant women, intake of NSS-sweetened beverages was not associated with the risk of developing gestational diabetes (adjusted relative risk [RR] 0.92; 95% CI 0.81, 1.04) (217); a cross-sectional study also found no association (218). A separate cross-sectional study did identify an association between NSS-sweetened beverages and gestational diabetes in 376 pregnant women attending a diabetes clinic for routine screening for gestational diabetes (adjusted OR 1.77; 95% CI 1.09, 2.86) (219).

3.3.2 Birth outcomes

3.3.2.1 Preterm birth

Three prospective cohort studies reported on use of NSS-sweetened beverages during pregnancy and preterm delivery (220–222). Results of meta-analysis suggest that NSS intake during pregnancy is associated with a 25% increase in risk of preterm birth (Fig. 34). A dose–response relationship was observed in the two studies that reported a significant association. Additional analyses suggested that the association was primarily for late preterm delivery (between weeks 34 and 37), not early preterm delivery (<32 weeks), and that the association was similar for lean and overweight women (220, 221). Analyses in one of the studies further suggested that the preterm delivery associated with intake of NSS-sweetened beverages was primarily medically induced delivery rather than spontaneous preterm delivery, although adjustment for hypertension and removal of women with diagnosed pre-eclampsia did not alter the effect significantly (221). A cross-sectional study reported no difference in gestational age at delivery between highest and lowest consumers of NSS-sweetened beverages (218).

1 PPVT-III: Peabody Picture Vocabulary Test-III; WRAVMA: Wide Range Assessment of Visual Motor Ability; KBIT-II: Kaufman Brief Intelligence Test 2nd edition; WRAML: Wide Range Assessment of Memory and Learning.

39 3. Results

Fig. 34. Association between NSS intake and risk of preterm birth

3.3.2.2 Birthweight

A secondary analysis of the cluster-randomized GeliS trial, which assessed the effects of a healthy lifestyle during pregnancy, found that intake of NSS-sweetened beverages during pregnancy was not associated with birthweight or BMI, or categorical assessments of low or high birthweight, or small or large for gestational age (223).

In a Dutch cohort of pregnant women, intake of NSS-sweetened products before conception was associated with increased birthweight (adjusted z-score coefficient per 10 g per 1000 kcal/day: 0.001; 95% CI 0.000, 0.001; P = 0.002) (224).
3.3.2.3 Large for gestational age

In a cohort study with women with gestational diabetes in Slovenia, intake of low-calorie beverages1 was not associated with large for gestational age (Spearman correlation 0.118; P nonsignificant) (225).

3.3.3 Health effects in offspring

3.3.3.1 Adiposity

In a prospective cohort study of pregnant women conducted in Canada, daily intake of NSS- sweetened beverages during pregnancy (compared with less than one serving per month) was associated with a 0.2 increase in infant BMI z-score (95% CI 0.02, 0.38) and a more than twofold increase in risk of overweight at 1 year of age (adjusted OR 2.19; 95% CI 1.23, 3.88). Adjustment for maternal BMI, diet quality, total energy intake or other obesity risk factors did not change the results (226).

In a prospective cohort study conducted in the United States, consumption of NSS-sweetened beverages during pregnancy was not associated with BMI z-score or waist circumference in offspring at mid-childhood (median age: 7.7 years) (227).

In a prospective cohort study conducted in Denmark, the children of women with gestational diabetes who consumed more than one NSS-sweetened beverage per day (compared with never) had a higher BMI z-score (b 0.59; 95% CI 0.23, 0.96) and risk of overweight or obesity (RR 1.93; 95% CI 1.24, 3.01) at 7 years of age (228).
3.3.3.2 Neurocognition

In a prospective cohort study following children in utero up to 7 years of age, early and mid- childhood cognition scores were inversely associated with maternal intake of NSS-sweetened beverages during pregnancy (PPVT-III,2 early childhood: –1.2; 95% CI –2.9, 0.5; total WRAVMA,
1. 1 Based on the reporting of other beverage types in this study, it was determined that “low-calorie beverages” consisted primarily, if not entirely, of NSS-sweetened beverages.
2. 2 PPVT-III: Peabody Picture Vocabulary Test-III; WRAVMA: Wide Range Assessment of Visual Motor Ability; KBIT-II: Kaufman Brief Intelligence Test 2nd edition; WRAML: Wide Range Assessment of Memory and Learning.

40 Health effects of the use of non-sugar sweeteners

early childhood: –1.5; 95% CI –2.9, –0.1; KBIT-II verbal, mid-childhood: –3.2; 95% CI –5.0, –1.5; KBIT-II nonverbal, mid-childhood: –2.0; 95% CI –4.3, 0.2; WRAVMA drawing, mid-childhood: –1.7; 95% CI –4.1, 0.6; WRAML visual memory, mid-childhood: –0.1; 95% CI –0.7, 0.5); however, there was no association between early and mid-childhood cognition scores and childhood NSS- sweetened beverage intake at 3 years (215).

3.3.3.3 Asthma

In a Danish birth cohort, the association between intake of NSS-sweetened beverages during pregnancy and child asthma at 1.5 years and 7 years was assessed. Consumption of more than 1 serving/day of NSS-sweetened beverages during pregnancy was associated with higher odds of the child having asthma at 18 months of age (adjusted OR 1.14; 95% CI 1.00, 1.28) and at 7 years of age (adjusted OR 1.20; 95% CI 1.07, 1.35) (229).
3.3.3.4 Allergies

In a Danish birth cohort, intake of more than 1 serving/day of NSS-sweetened beverages during pregnancy was associated with statistically nonsignificant higher odds of the child ever having allergic rhinitis by 7 years of age (OR 1.11; 95% CI 0.86, 1.43) (229).
3.3.3.5 Adverse effects

In a Norwegian birth cohort study, intake of artificially sweetened beverages during pregnancy was not significantly associated with higher risks of congenital heart disease in the offspring (adjusted OR 0.95–0.96, nonsignificant) (230), nor was consumption of NSS-sweetened beverages in a Danish cohort (≥4 servings/day versus no use; for carbonated beverages, adjusted OR 1.01; 95% CI 0.32, 3.21; Ptrend 0.06; for noncarbonated beverages, adjusted OR 1.08; 95% CI 0.65, 1.80; Ptrend 0.72) (231).

A case–control study found no significant association of spontaneous abortion with intake of saccharin during pregnancy (232).

3.3.4 Additional outcomes1

3.3.4.1 Gestational weight gain

In the TOP study (RCT) in Denmark, gestational weight gain and risk for excessive gestational weight were higher in pregnant women consuming NSS ≥1/day compared with 0/day (MD 2.0 kg; 95% CI –0.2, 4.2; and RR 1.50; 95% CI 1.17, 1.92, respectively) (233).

In a cohort study with women with gestational diabetes in Slovenia, gestational weight gain was not significantly associated with intake of low-calorie beverages2 (Spearman correlation 0.118; P nonsignificant) (225).

In a prospective cohort study in Iceland (the PREWICE cohort), pregnant women with excessive gestational weight gain consumed more NSS-sweetened beverages (median: 0.5 times per week; interquartile range [IQR] 0.1 to 2.0; P < 0.01) than those with optimal and suboptimal gestational weight gain (median 0.1; IQR 0.1 to 1.0) (234).

1 Not specified a priori.
2 Based on the reporting of other beverage types in this study, it was determined that “low-calorie

beverages” consisted primarily, if not entirely, of NSS-sweetened beverages.

41 3. Results

3.3.4.2 Cardiometabolic health (maternal)

In a cohort study of women with gestational diabetes in Denmark, intake of two or more NSS- sweetened beverages per week during and after pregnancy (when compared with four or fewer per month) was associated with significantly higher HbA1c (6.0%; 95% CI 2.8, 9.1), fasting glucose (7.1 mmol/L; 95% CI 2.2, 12.4) and obesity (RR 1.37; 95% CI 1.04, 1.81), but no significant difference in fasting insulin, HOMA-IR, triglycerides, HDL cholesterol, LDL cholesterol, BMI, waist circumference or type 2 diabetes (235).

42 Health effects of the use of non-sugar sweeteners

4. Discussion Summary of results

This systematic review of a large number of RCTs, prospective cohort studies and case–control studies found that NSS use results in a small reduction in body weight and BMI in adults, as assessed in RCTs (low certainty evidence) without significant effects on other measures of adiposity or cardiometabolic health, including fasting glucose, insulin, blood lipids and blood pressure (very low to high certainty evidence). The effects appear more pronounced when NSS are compared with sugars, and it is likely that they are mediated by a reduction in energy intake, which is only observed in studies in which NSS are compared to sugars. When NSS are used specifically as replacements for sugars (mostly in the form of replacing SSBs with NSS-sweetened beverages), the effects on body weight and BMI are smaller, and neither are statistically significant (moderate certainty evidence).

Results from prospective cohort studies suggest that higher NSS intake is associated with increased body weight, and increased risk of type 2 diabetes, cardiovascular diseases and all- cause mortality (very low to low certainty evidence). Results from case–control studies suggest an association between saccharin intake and bladder cancer (very low certainty evidence), but significant associations for other types of cancer were not observed in case–control studies or meta-analysis of prospective cohort studies (very low to low certainty evidence).

Relatively fewer studies were found for children, and results were largely inconclusive. One fairly large, well-conducted RCT in which SSBs were replaced with NSS-sweetened beverages reported a small reduction in measures of adiposity (moderate certainty evidence). However, the effect was not observed when this study was meta-analysed with another study, and was not corroborated by results from prospective cohort studies.

Results for pregnant women suggest that higher NSS intake is associated with increased risk of preterm birth (low certainty evidence) and possibly adiposity in offspring (very low certainty evidence).

Interpretation

The results suggest that, in the short term, NSS use may lead to small reductions in adiposity without any significant impact on cardiometabolic risk. There is suggestion of negative health effects with long-term use, but the evidence is ultimately inconclusive.

That a difference in body weight with NSS intake was observed in shorter term RCTs, primarily when NSS were compared with sugars, is not unexpected given current knowledge regarding the role of sugars in unhealthy weight gain, particularly when they are consumed in beverage form. Evidence suggests that the body does not sense calories from SSBs in the same manner as those in solid foods, in terms of satiety (236) – as a result, they are not compensated for by a reduction in energy intake in the rest of the diet, thus leading to positive energy balance. Because most of the studies included in this review that compared NSS with sugars did so by providing NSS-sweetened beverages or SSBs as a supplement to the existing diet, it is likely that those receiving the SSBs did not fully compensate for the extra calories from the added sugars, whereas those receiving NSS-sweetened beverages were not consuming these extra calories. This is supported by the observation that energy intake was significantly higher in those not receiving NSS, exclusively in studies that compared NSS with sugars. Because the effects of NSS on adiposity were smaller for studies in which NSS were used specifically as a replacement for

43 4. Discussion

sugars, it may be that the effects observed for NSS compared with sugars in the main analyses are being driven in part by the inability to compensate for added sugars rather than the ability of NSS to limit energy intake per se, and consequently weight gain.

In contrast to the shorter-term effects on adiposity observed in RCTs, longer-term cohort data with follow-up to 10 years, while more limited, suggest increased risk of adiposity with higher NSS intake. Although long-term data from RCTs are limited, two trials were identified that lasted 1 year or more (the duration of most of the RCTs was less than 6 months) (22, 180). Both trials reported a modest reduction in body weight, although one trial, which consisted of active weight loss with or without NSS for 16 weeks followed by 12 months of active maintenance and another 18 months of post-trial follow-up, reported significant differences only at the two latter time points: weight loss was similar between NSS and no NSS at the end of the 16-week active weight loss phase (22). Two additional trials lasting 12–18 months were included; however, they both tested the effects of asking habitual NSS users to switch to water (and reported vastly different results), and therefore do not directly provide insight on how longer-term use of NSS affects adiposity.

Differences were also seen between RCTs and prospective cohort studies in the effect of NSS use on intermediate markers of diabetes and cardiovascular diseases and incident disease. RCTs found no such effects, whereas positive associations were observed in the prospective cohort studies between NSS use and mortality and disease.

The reason for the discrepancy between the results of the RCTs and prospective cohort studies is unclear, although reverse causation has been noted as a possible explanatory factor for the observed associations in cohort studies (237, 238). In the context of NSS, reverse causation implies that individuals assessed as higher consumers of NSS at baseline have recently experienced changes in body weight, are already in a “predisease” state or are otherwise at high risk for disease (e.g. overweight, elevated risk factors) and, in response, have initiated or increased NSS intake, thus leading to a spurious association between NSS intake and increased body weight, mortality or disease. Indeed, in some studies, those with the highest intakes of NSS had higher body weight or BMI, had poorer overall diet quality, or were at higher risk for disease at baseline than those with lower intakes, and associations between NSS and disease outcomes only remained significant in those with higher BMIs when results were stratified by BMI, suggesting that reverse causation may be contributing to the observed association. However, other studies reported no significant baseline imbalances between highest and lowest consumers of NSS, and/ or lower risk for disease among highest consumers of NSS at baseline (e.g. better diet quality, more exercise, less smoking). The greater association of NSS use in people with higher BMI can be interpreted either as an indication of reverse causation or as NSS contributing to weight gain as an intermediate step along the pathway to disease.

Recognizing that reverse causation might be particularly relevant for NSS, many of the authors of the cohort studies took great lengths to address it. They undertook extensive adjustments for potential confounders and robust sensitivity analyses to test the impact of removing data that might contribute to reverse causation – for example, excluding data from the first several years after baseline assessment, or from participants with identified risk factors for disease, or who had experienced unplanned weight change prior to baseline assessment. In the case of type 2 diabetes and stroke, the positive association remained in the majority of studies that performed such analyses, and in some cases strengthened. In addition, more than half the cohort studies assessing the effects of NSS on incident type 2 diabetes that reported a Ptrend value reported a statistically significant Ptrend, suggesting the possibility of a dose–response relationship. The results of these additional analyses are difficult to reconcile with reverse causation being the sole cause of the positive association between NSS use and type 2 diabetes as it would suggest a long latency period before manifestation of disease, and that those at increasingly greater risk of disease at baseline would have consumed proportionately more NSS, which is possible but not necessarily self-evident or logically explained. The results of similar sensitivity analyses for

44 Health effects of the use of non-sugar sweeteners

mortality and cardiovascular diseases are not as consistent, but also do not rule out a bona fide association between NSS intake and increased risk.

Although the discordant results between shorter-term RCTs and longer-term cohort studies may be partially or largely a result of reverse causation and/or residual confounding, an alternative explanation may be found in likely differences in how NSS were consumed between the experimental settings of RCTs and in free-living populations as assessed in prospective cohort studies. In most of the RCTs included in this review, NSS were consumed as an alternative to sugars, and, in many, NSS were provided directly as a stand-alone item (mostly beverages) to consume. Although it is not known how the NSS in every trial were actually consumed, given the design of many of the trials, it is reasonable to assume that the NSS were generally treated as an experimental food or beverage to be consumed, likely on its own, and in many cases specifically as a replacement for sugars. In contrast, real-world consumption of NSS as assessed in cohort studies is more complex and could follow a variety of patterns including as a conscious, specific replacement of sugars, but also as a general part of the diet without concern for whether or not they are replacing sugars, or have low or no calories. NSS could also be used as a justification for consuming other sugary or unhealthy foods – that is, people who have consumed a food or beverage with NSS might feel that it is acceptable to then consume sugar-containing (or otherwise unhealthy) foods or drinks (239). Evidence does suggest that many people consume products with NSS not in replacement of, but in addition to, foods containing sugars, as well as other unhealthy foods (240–242), and results of a cross-sectional study of children completing the NHANES survey in the United States suggest that consuming both NSS and sugars is associated with greater total energy intake than consuming either alone (242). The effects of consuming NSS and sugars together have also been explored in a recent RCT (included in this review) that reported that the intake of sucralose alone does not impair insulin sensitivity, but, when consumed together with another carbohydrate (maltodextrin), it both impairs insulin sensitivity and decreases the neural response to sugars intake, suggesting that sucralose, when consumed with carbohydrates, disrupts gut–brain regulation of glucose metabolism (100). Evidence for effects of regularly consuming NSS and sugars together is very limited, and further research is clearly needed. However, these results do suggest a possible explanation for some of the differences observed between the RCTs and prospective cohort studies.

Mechanisms by which NSS as a class of molecules might exert effects that increase risk for obesity and certain NCDs have been reviewed extensively and include interaction with extra- oral taste receptors (243), possibly with alteration of the gut microbiome (244). Because sugars and all known NSS presumably elicit sweet taste through the TAS1R heterodimeric sweet-taste receptor (245), which has been identified not just in the oral cavity but in other glucose-sensing tissues (243), it is not surprising that such a group of vastly different chemical entities could be responsible for similar effects on health. However, as NSS are a diverse group of molecules, the magnitude or precise effects on disease risk might differ slightly, and off-target interactions (i.e. interactions other than with the sweet-taste receptor) could differ significantly between individual NSS (246). Several of the RCTs included in this review used individual sweeteners, but the limited meta-analyses did not suggest any striking differences, although a small number of studies included in the review concluded that there appeared to be NSS-specific differences in effects on body weight, for example. Virtually none of the cohort studies reported on individual NSS as exposures.

The results of the review suggest an association between NSS intake and risk of bladder cancer, with the effect being almost entirely driven by use of saccharin, primarily via tabletop use (i.e. added by the consumer). The results were unexpected given that, despite early concerns regarding a possible link between saccharin and bladder cancer based on results of studies in rodents (247), subsequent studies in humans failed to replicate the findings (248). A 2015 systematic review on NSS intake and cancer did not find an association between NSS intake and bladder cancer; however, the review included only five studies in total (249). A number of the

45 4. Discussion

studies included in the current review are decades old; many lack important details, including information on doses being consumed in the studies; and nearly half have serious risk of bias. As a result, confidence (certainty) in the results for bladder cancer is very low, and therefore the results must be interpreted cautiously.

The results for pregnant women require further scrutiny, but are in line with a recent study that provided supporting mechanistic data from animal and in vitro studies regarding a possible association between NSS intake during pregnancy and childhood adiposity (250). Although there are questions about the nature of the association observed between NSS intake during pregnancy and preterm birth, including potential mechanisms, the recent finding from a systematic review of an association between preterm birth and childhood obesity (251) draws a link between the two main observations in this review for NSS intake during pregnancy. Given that NSS use may be increasing among pregnant women (10), further research is needed to confirm the findings for pregnant women.

Agreement with other recent systematic reviews

Result of this review largely agree with those of other recent systematic reviews, in that replacing sugars with NSS in the short term results in reductions in body weight, with little impact on other cardiometabolic risk factors, but is associated with increased risk of type 2 diabetes, cardiovascular diseases and mortality in the longer term.

As in the current review, a 2021 systematic review and meta-analysis of NSS consumption and body weight and energy intake in intervention studies found that body weight, BMI and energy intake were lower among those receiving NSS when compared with sugars, but not water (252). Similarly, a 2020 systematic review of the effects of NSS intake on body weight as assessed in RCTs found a small reduction in body weight with NSS intake, which was strongest in overweight and obese individuals, and when NSS replaced sugars (253). Similarly, the review did not find a significant pooled effect on body weight in children. Strong similarity in results between previous reviews and the current review are observed despite less restrictive inclusion and exclusion criteria in the earlier reviews (e.g. inclusion of trials that were not randomized (254), employed doses that exceeded the ADI (255), included exclusively pre-diabetic or diabetic participants (256), or used interventions where the effects of NSS could not be isolated, such as replacement of SSBs with “noncaloric beverages” (257, 258), which resulted in slightly different, but largely the same, sets of studies for each outcome between the earlier reviews and the current one). A 2018 systematic review of observational studies found a significant association between NSS use and increased BMI in children (259); however, the review included three cross-sectional studies in the meta-analysis that showed fairly large associations between NSS intake and BMI, which is likely to have skewed the results (the three studies accounted for 32% of the weight in the meta- analysis). Because it is very likely, especially in children, that consumption of NSS is initiated as a result of weight gain, cross-sectional studies are not an informative study design for assessing causation; we therefore did not include them in assessing body weight outcomes.

Three systematic reviews with dose–response meta-analyses published in 2021 found significant associations between consumption of NSS-sweetened beverages and all-cause and cardiovascular disease mortality. However, there was some inconsistency between the studies in the nature of the identified dose–response relationships, with some reporting linear relationships and others reporting J-shaped or nonlinear relationships (260–262). Two of these reviews that also assessed the effects of consumption of NSS-sweetened beverages on cancer mortality found no evidence of an association. Similarly, a 2021 systematic review and meta-analysis of NSS consumption and gastrointestinal cancer as assessed in cohort and case–control studies found no association (263).

A 2017 systematic review assessing body weight and disease outcomes in studies with a minimum duration of 6 months found significant associations between higher NSS intake and increased risk of incident obesity, type 2 diabetes, hypertension, cardiovascular events and stroke (264). A

46 Health effects of the use of non-sugar sweeteners

nonsignificant reduction in body weight as assessed in RCTs was reported; however, the review included only five RCTs reporting on body weight, far fewer than the number included in the current review. A 2017 systematic review of the effects of NSS on measures of glycaemic control found that NSS intake did not appreciably effect blood glucose levels (265). Similarly, a 2021 systematic review and meta-analysis of NSS consumption and chronic kidney disease in cohort and case–control studies found no association between NSS consumption and risk of chronic kidney disease; however, dose–response analysis suggested increased risk above seven servings of NSS per week (266).

A 2021 systematic review on the effects of NSS use during pregnancy and birth outcomes found significant associations between NSS use and increased risk of preterm birth, decrease in gestational age and increased birthweight (267). A 2016 systematic review on the effects of early exposure to NSS (including use during pregnancy) on longer-term metabolic outcomes did not identify any studies that reported on NSS use during pregnancy and metabolic outcomes in offspring (268). The current review also found an association between NSS use and preterm birth, as well as a suggestion of slightly increased adiposity later in childhood, although the data for the latter and other birth outcomes were not amenable to meta-analyses.

Strengths and limitations

The strengths of this review are breadth and depth of the data identified from different study types, and rigorous assessment of the certainty in the evidence via the GRADE framework. Limitations include our inability to meta-analyse a significant portion of the data, particularly outcomes measured predominantly in subjective terms. In addition, because a head-to-head comparison of NSS vs water as replacement for SSB was not prioritized by the NUGAG Subgroup, we were unable to fully account for the effects of water compared with NSS-sweetened beverages as a replacement for SSBs – that is, our literature search strategy was not designed to identify studies that exclusively assessed water as a replacement, without NSS as a comparator.1 We were also limited in our ability to assess potentially differential health effects of individual sweeteners, and while very few of the cohort studies provided detail on specific sweeteners as exposures, it is likely that in most studies, especially those with many years of follow-up, NSS consumed were primarily those that have been on the market for many years, and that newer sweeteners were less well represented.

Because so many different interventions and experimental designs were employed to assess the effects of NSS intake in the included RCTs, it was difficult to relate the pooled effects to the primary interest of NSS as a replacement for sugars in the context of body weight. Although a small number of studies specifically assessed the effects on habitual users of sugar-sweetened foods and beverages of replacing these foods and beverages with NSS-sweetened alternatives, most trials provided NSS or sugars as an addition to the diet, others provided nothing or water as the comparator, still others provided NSS in capsule form, and a small number assessed the inclusion of NSS in the context of a calorie restricted diet. In addition, two trials assessed the effects of asking habitual users of NSS-sweetened beverages to switch to water. As a result, the majority of the available evidence for effects of NSS used as a replacement for sugars on measures of adiposity is indirect.

Concluding remarks

The results of this review suggest that, in shorter-term RCTs, those consuming NSS had lower body weight and BMI at the end of the trials than those not consuming NSS, particularly when compared with sugars (including when NSS were explicitly used as replacements for sugars), but not when compared with water. Those consuming NSS also exhibited a significant reduction in energy intake, primarily when NSS were compared to sugars. Therefore, NSS may be effective at

1 The search strategy employed in the original systematic review (1) was also not designed to identify studies that exclusively assessed water as a replacement, without NSS as a comparator.

47 4. Discussion

assisting with short-term weight loss when their use leads to a reduction in total energy intake. Results from prospective cohort studies suggest the possibility of long-term harm in the form of increased risk of obesity, type 2 diabetes, cardiovascular diseases and mortality. Further research is needed to determine whether the observed associations are genuine or a result of reverse causation and/or residual confounding. Further research is also needed in children and pregnant women, the latter for which prospective cohort studies currently suggest possible unfavourable effects of NSS consumption on birthweight and adiposity in offspring later in life.

48 Health effects of the use of non-sugar sweeteners

ANNEX 1.

Search strategies

The following search terms were used to search the respective databases as indicated.

MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations (Ovid), and Embase (Ovid)

1 artificial sweetener*.mp.
2 exp Aspartame/
3 aspartame.mp.
4 acesulfame.mp.
5 Ace K.mp.
6 Saccharin/
7 saccharin*.mp.
8 neotame.mp.
9 sucralose.mp.
10 advantame.mp.
11 Cyclamates/
12 cyclamate.mp.
13 alitame.mp.
14 neohesperidin.mp.
15 stevia.mp.
16 Stevia/
17 steviol*.mp.
18 stevioside*.mp.
19 rebaudioside*.mp.
20 rebiana*.mp.
21 thaumatin*.mp.
22 brazzein*.mp.
23 mogroside*.mp.
24 sweetening agent/ or non-nutritive sweetener/ or nutritive sweetener/
25 ((non-calori* or noncalori*) adj (sweetener* or sweetner*)).mp.
26 ((non-sugar or nonsugar) adj (sweetener* or sweetner*)).mp.
27 ((non-nutritive or nonnutritive) adj (sweetener* or sweetner*)).mp.
28 ((low-calori* or lowcalori*) adj (sweetener* or sweetner*)).mp.
29 ((intense or high intensity or high potency) adj3 (sweetener* or sweetner*)).mp.
30 natural sweetener*.mp.
31 nonnutritive sweetener/

49 Annex 1. Search strategies

32 natural sweetening agent*.mp.
33 ((non-caloric or noncaloric) adj (beverage* or drink* or soft drink*)).mp.
34 sugar substitute*.mp.
35 (diet soda*).mp
36 (diet beverage*).mp
37 (diet drink*).mp
38 (diet cola*).mp
39 (sugar-free).mp
40 (calorie-free).mp
41 (artificially sweetened).mp
42 (non-nutritively sweetened).mp
43 (non-calorically sweetened).mp
44 (Low calorie beverage).mp
45 (Low calorie drink).mp
46 (Low calorie soda).mp
47 or/1-46
48 exp animals/ not humans.mp.
49 47 not 48
50 limit 49 to yr=”2017 -Current”
51 or/1-40
52 51 not 48
53 49 not 52

Cochrane CENTRAL

#1 “artificial sweetener*”
#2 MeSH descriptor: [Aspartame] explode all trees
#3 aspartame
#4 acesulfame
#5 “Ace K”
#6 MeSH descriptor: [Saccharin] this term only
#7 saccharin
#8 neotame
#9 sucralose
#10 advantame
#11 MeSH descriptor: [Cyclamates] explode all trees
#12 cyclamate
#13 alitame
#14 neohesperidin
#15 MeSH descriptor: [Sweetening Agents] this term only
#16 MeSH descriptor: [Non-Nutritive Sweeteners] this term only

50 Health effects of the use of non-sugar sweeteners

#17 MeSH descriptor: [Nutritive Sweeteners] this term only
#18 stevia
#19 MeSH descriptor: [Stevia] this term only
#20 steviol*
#21 stevioside*
#22 rebaudioside*
#23 rebiana*
#24 thaumatin*
#25 brazzein*
#26 mogroside*
#27 (non-calori* or noncalori*) near (sweetener* or sweetner*)
#28 (non-sugar or nonsugar) near (sweetener* or sweetner*)
#29 (non-nutritive or nonnutritive) near (sweetener* or sweetner*)
#30 (low-calori* or lowcalori*) near (sweetener* or sweetner*)
#31 (intense or high intensity or high potency) near/3 (sweetener* or sweetner*)
#32 “natural sweetener*”
#33 “natural sweetening agent*”
#34 (non-caloric or noncaloric) near (beverage* or drink* or soft drink*)
#35 “sugar substitute*”
#36 “diet soda*”
#37 “diet beverage*”
#38 “diet drink*”
#39 “diet cola*”
#40 “sugar-free”
#41 “calorie-free”
#42 “artificially sweetened”
#43 “non-nutritivelysweetened”
#44 “non-caloricallysweetened”
#45 “Low calorie beverage”
#46 “Low calorie drink”
#47 “Low calorie soda”
#48 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15or#16or#17or#18or#19or#20or#21or#22or#23or#24or#25or#26or#27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 [limited to Jan 2017 – present]
#49 #48 NOT the original search (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11or#12or#13or#14or#15or#16or#17or#18or#19or#20or#21or#22or#23 or#24or#25or#26or#27or#28or#29or#30or#31or#32or#33or#34or#35)[no time limits]
#50 #48 OR #4

51 Annex 1. Search strategies

Other

Mortality

Sweet
preference

Eating
behaviour

Allergy

Asthma

CKD (+
markers)

Cognition

Behaviour

Mood

Dental
health

Cancer

Stroke

CHD

CVD
(+ markers)

Diabetes
(+ markers)

Weight
(+ markers)

Population and study design Adults

0
0
6
9
0
1
0
2
1
2
5
2
0
0
3
4
31
Children

0
0
3
5
0
0
1
0
0
0
0
0
0
0
1
2
8
Mixed

8
0
0
0
1
1
0
1
0
0
0
0
0
0
1
3
8
Pregnant women

8
8
34
59
1
2
8
8
2
10
6
56
2
4
56
83
135
Total

ANNEX 2. Outcomes reported by study design and population

Case–controlstudy 1 1 0 0 0 42 0 0 0 0 1 0 0 0 0 0 0 Cohort study 18 15 12 4 2 12 0 3 0 2 2 0 0 1 0 8 0 Controlledtrial 31100000000003100

Cross-sectionalstudy
24 18 9 0 0 0 0 1 1 0 1 0 0 12 8 0 0 Randomizedcontrolledtrial
36 26 23 0 0 0 1 4 0 2 2 0 0 27 16 0 0 Randomized controlled trial (ongoing)
5 1250 0 0 0 0 0 1 1 0 0200 0 Controlledtrial(ongoing) 11100000000000000

Case–controlstudy 00000200000000000 Cohort study 14 1 1 0 0 0 1 0 0 0 0 0 0 4 2 0 0 Controlledtrial 01000001110001000

Cross-sectionalstudy
Randomizedcontrolledtrial
Randomizedcontrolledtrial(ongoing)

Cohort study
Cross-sectionalstudy
Randomizedcontrolledtrial

Case–controlstudy
Cohort study
Cross-sectionalstudy

15 1 2 0 0 0 2 1 0 0 0 1 0 1 3 0 0 20000020010002000 0 1 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0

10000000000000000 71000000000004300 01100000001001000

00000000000000001 82100000010110005 01000000000000002

CHD: coronary heart disease; CKD: chronic kidney disease; CVD: cardiovascular diseases.

52 Health effects of the use of non-sugar sweeteners

DESCRIPTION

ADULTS

DURATION

7 days (3 days washout)	6 months	3 weeks	8 weeks	3.5 years (3 weeks washout + 16 weeks intervention + 1 year maintenance program + 2 years additional follow-up)
Sugars	Sugars, water	Fructose	Sucrose	Avoiding aspartame
Tabletop	Soft drink	Water	Drink	Drink, food, tabletop
Stevia	Unspecified	Sucralose	Aspartame	Aspartame
19–60	–	–	30–55	43–55
16 (mixed)	71 (mixed)	118 (mixed)	40 (male)	163 (female)
Mixed	Mixed	Mixed	Overweight	Overweight
Crossover	Parallel (abstract only)	Parallel	Parallel (abstract only)	Parallel
–	–	–	–	1988
United Kingdom	United States	United States	United Kingdom	United States

COMPARA- TOR(S)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

DESIGN

STUDY START (YEAR)

COUNTRY

STUDY

ANNEX 3. Characteristics of included studies

Table A3.1 Randomized controlled trials

Al-Dujaili 2017

(48)

Angelopoulos
2015, 2016a,
2016b (73, 74,
269)

Baird 2000 (70)

Ballantyne 2011

(71)

Blackburn 1997

(22)

Provision of stevia (600 mg/day) or sugars (15 g/day) to be used preferably in a hot drink. Avoidance of other forms of sweeteners or sugars during the study.

Provision of two 12-ounce servings of artificially-sweetened, sugar- sweetened or unsweetened beverages per day with American Dietetic Association (ADA) exchange diet.

Provision of water solution with sucralose (125, 250 and 500 mg/day during weeks 1–3, 4–7 and 8–12, respectively) or fructose. Highest dose (500 mg) is likely above ADI (5 mg/day/kg), and mean weight of participants is 70 kg; therefore data not extracted for this dose.

Provision of aspartame- or sucrose-sweetened drinks (250 mL) 4× per day. All participants were informed that they were receiving sugars drinks (i.e. half the participants were misinformed).

All participants followed a weight loss program. Participants in the aspartame arm were given aspartame-sweetened pudding, milkshakes and noncarbonated beverage mix; and packets of tabletop sweetener. The no-aspartame arm was told to avoid products sweetened with any low-energy sweetener and to use sugars or honey instead, and were given a non-energy-containing flavoured seltzer water to drink instead of diet soda. Data from the 2-year follow-up were included in the main analysis.

53 Annex 3. Characteristics of included studies

DESCRIPTION

DURATION

12 weeks	10 weeks	12 weeks	8 weeks	2 weeks	1 year	6 months	5 weeks	12 weeks
Water	Placebo	Sugars	Sugars	Sucrose	SSB, water	SSB, water, milk	Water	D-allulose
Soft drink	Drink	Soft drink	Soft drink	Soft drink	Soft drink	Soft drink	Soft drink	Soft drink
Aspartame, acesulfame K	Sucralose	Unspecified	Unspecified	Sucralose	Unspecified	Aspartame	Acesulfame K+ aspartame + sucralose	Sucralose
31 (mean)	18–35	20–43	–	20–45	18–40	20–50	18–45	20–40
50 (mixed)	137 (mixed)	31 (mixed)	–	39 (mixed)	203 (mixed)	73 (mixed)	166 (mixed)	121 (mixed)
Mixed	Lean	Overweight	Mixed	Mixed	Mixed	Overweight	Lean	Mixed
Crossover	Parallel	Parallel	Parallel (abstract only)	Parallel	Parallel	Parallel	Crossover	Parallel
2012	2016	2011	–	2015	2011	2008	2014	2016
France	Mexico	Switzer- land	Unclear	United States	United States	Denmark	France	Republic of Korea

COMPARA- TOR(S)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

DESIGN

STUDY START (YEAR)

COUNTRY

STUDY

Bonnet 2018 (SEDULC) (26)

Bueno-Hernández 2020 (53)

Campos 2015
(REDUCS study)
(27)1

Crutchley 2013

(72)

Dalenberg 2020
(100)2

Ebbeling 2020
(BASH III) (180)3

Engel 2018 (23)4

Fantino 2018
(175)5

Han 2018 (29)

Provision of aspartame-sweetened (258 mg/ day) and acesulfame K-sweetened (26 mg/day) soda or water, 330 mL each, 2× per day.

Provision of bottles (60 mL) containing sucralose-sweetened water (62 or 123 mg/ day) or unsweetened water 9× per week.

Habitual consumers of SSBs were instructed to replace SSBs with artificially sweetened beverages, or not replace them. Provision of artificially and sugar-sweetened carbonated soft drinks and iced tea.

Replacement of SSBs with diet soft drinks.

Provision of sucralose-sweetened (60 mg/day) or sucrose-sweetened (30 g/day) beverages 7× over 2 weeks. The separate trial in adolescents was halted based on preliminary results of the trial in adults.

Habitual consumers of SSBs were instructed to replace SSBs with artificially sweetened beverages or unsweetened beverages (i.e. water: still or sparkling, with or without flavour). Provision of beverages.

Provision of sucrose-sweetened regular cola, aspartame-sweetened diet cola, water or semi-skimmed milk (1 L/day). Participants were allowed to drink water, coffee, tea and their regular amount of alcohol.

Provision of acesulfame K-, aspartame- and sucralose-sweetened lemonade or water (330 mL) 3× per day.

Provision of grapefruit-flavoured, noncarbonated bottled drink (2 × 30 mL), sweetened with either sucralose (24 mg/day) or the rare low-energy sugar D-allulose (8 g/ day or 14 g/day).

54 Health effects of the use of non-sugar sweeteners

DESCRIPTION

DURATION

12 weeks	12 weeks	2 months	12 weeks	4 months
Placebo	Sucrose	Sugars	Avoiding aspartame	Sugar- sweetened snack
Drink, capsule	Soft drink	Drink	Drink, food, tabletop	Food
Aspartame	Saccharin, aspartame, rebaudioside A , sucralose	Unspecified	Aspartame	Stevia
18–60	18–60	≥18	20–60	47 (mean)
100 (mixed)	154 (mixed)	158 (mixed)	59 (mixed)	38 (mixed)
Lean	Overweight	Mixed	Overweight	Metabolic syndrome
Parallel	Parallel	Parallel	Parallel	Parallel (abstract only)
2016	2016	–	1986	–
United States	United States	United Kingdom, United States	United States	Greece

COMPARA- TOR(S)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

DESIGN

STUDY START (YEAR)

COUNTRY

STUDY

Higgins 2018 (30)

Higgins 2019 (31)

Judah 2020 (181)

Kanders 1988

(32)

Kassi 2016 (49)

Provision of 1) 0 mg aspartame/day (2 capsules collectively containing 680 mg dextrose and 80 mg PABA, and 2 empty capsules); 2) 350 mg aspartame/day (sachets of flavoured dry powder beverage mixture reconstituted by participants to yield 500 mL, containing 350 mg aspartame and 80 mg PABA, 2 capsules collectively containing 680 mg dextrose and 2 empty capsules); or 3) 1050 mg aspartame/ day (sachets of flavoured dry powder beverage mixture reconstituted by participants to yield 500 mL, containing 350 mg aspartame and 80 mg PABA, 4 capsules collectively containing 700 mg aspartame and 680 mg dextrose).

Provision of 1.25–1.75 L/day of an equally sweet fruit-flavoured beverage with sucrose (100–140 g/day), saccharin (0.73 g/day), aspartame (0.58 g/day), rebaudioside A (0.66 g/day) or sucralose (0.16 g/day).

Participants were recruited online, and the intervention was delivered online. Regular consumers of SSBs were advised to substitute their SSBs with either water or diet drinks.

Provision of intervention arm’s milk exchanges as aspartame-sweetened pudding or milkshake. Participants were instructed to consume 2 per day and were encouraged to use low-calorie table sweetener, aspartame, diet sodas and gelatin as desired. Control arm avoided the use of all aspartame- or saccharin- sweetened products. Both arms followed a balanced deficit diet consisting of 1000 kcal for females and 1200 kcal for males.

Provision of a stevia-sweetened snack 4× per week or a sugar-sweetened snack 1× per week.

55 Annex 3. Characteristics of included studies

DESCRIPTION

DURATION

4 weeks	2 weeks	2 weeks	8 days	2 weeks	4 weeks	6 weeks
Sugars, fructo- oligosac- charide	Water	Placebo	Glucose, fructose	Sugars, fructo- oligosac- charide	Placebo	Sucrose
Drink	Soft drink	Capsule	Drink	Drink	Capsule	Tabletop
Aspartame	Acesulfame K+ aspartame	Acesulfame K + sucralose	Aspartame	Aspartame	Sucralose	Sucralose, stevia
College students	18–75	18–75	18–25	College students	≥18	18–35
51 (mixed)	39	36	10 (mixed)	51 (mixed)	15 (mixed)	39 (mixed)
Mixed	Mixed	Mixed	Lean	Mixed	Mixed	Lean
Parallel (abstract only)	Crossover	Parallel (abstract only)	Crossover	Parallel (abstract only)	Crossover	Parallel
–	2018	2015	2009	–	2016	–
Republic of Korea	Republic of Korea	Australia	United States	Republic of Korea	Thailand	Mexico

COMPARA- TOR(S)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

DESIGN

STUDY START (YEAR)

COUNTRY

STUDY

Kim 2011 (33)

Kim 2020 (51)

Kreuch 2020 (99)

Kuzma 2015 (34)

Lee 2012 (95)

Lertrit 2018 (35)

López-Meza 2021

(270)

Provision of 2 drinks (700 mL) per day sweetened with aspartame, sugar, low- fructo-oligosaccharides or high-fructo- oligosaccharides. The comparison aspartame versus sugars was extracted.

Participants were assigned to 0.6 L/day of artificially sweetened soft drink with acesulfame K (126.6 mg/day) and aspartame (86.4 mg/day), or mineral water for 2 weeks, in a crossover study, with a 4-week washout period.

Participants were assigned to capsules containing NSS (92 mg sucralose and 52 mg acesulfame K) or placebo, 3× per day for 2 weeks.

Provision of 4 servings per day of an equally sweet beverage sweetened with fructose, glucose or a low-calorie sweetener (Equal, primarily aspartame). Provision of food. Crossover trial separated by 20 days washout. We compared aspartame vs fructose and glucose.

Provision of aspartame, sugar, low- fructo-oligosaccharides, high-fructo- oligosaccharides, or low fructo- oligosaccharides with milk. Mode of delivery was unclear.

Provision of hard gelatin capsules (1× per day) with sucralose (200 mg) or empty capsules.

Participants underwent a 1-week washout period, then were divided into three arms receiving packets of sucrose, sucralose or steviol glycosides each day for 6 weeks.

56 Health effects of the use of non-sugar sweeteners

DESCRIPTION

DURATION

18 months (6 months weight loss + 12 months weight maintenance)	8 weeks (4 weeks washout)	8 weeks	6 weeks (4 weeks washout)	1 year (12 weeks weight loss + 40 weeks weight maintenance)
Water	Sugars	Sugar, maltodex- trin	Sugars	Water
Drink	Drink, food, capsule	Soft drink	Hot drink	Soft drink
Unspecified	Unspecified	Acesulfame K+ aspartame	Unspecified	Unspecified
18–50	20–49	20–55	40–64	21–65
89 (female)	50 (mixed)	118 (mixed)	44 (mixed)	303 (mixed)
Overweight	Mixed	Mixed	Overweight	Overweight
Parallel	Crossover	Parallel (PhD thesis)	Crossover	Parallel
2014	2012	2010	2005	2012
Iran (Islamic Republic of)	United Kingdom	New Zealand	United States	United States

COMPARA- TOR(S)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

DESIGN

STUDY START (YEAR)

COUNTRY

STUDY

Madjd 2018 (36)6

Markey 2016
(REFORM) (37)

McLay-Cooke
2016 (Ice Tea
Study) (38)

Njike 2011 (39)

Peters 2016 (40)7

Habitual NSS users consumed either 250 mL diet beverage after main meal 5× per week (and the rest of beverages was water) or consumed only water (no other drinks). Both arms avoided consuming beverages during the meal and adding low-calorie sweeteners to tea/coffee, and were instructed to follow a hypoenergetic diet and increase activity levels.

Provision of regular diet (with sugar- sweetened foods and drinks) or a reformulated diet (with sugar-reduced foods and drinks).

Provision of diet (acesulfame K and aspartame) or regular (sugar and maltodextrin) soft drinks, 500 mL per day.

Provision of hot cocoa beverages (2× per day): 1) sugar-free cocoa (cocoa powder + unspecified NSS), 2) sugar-sweetened cocoa (cocoa powder + 45.5 g sugar), 3) placebo (0 cocoa powder + 55 g sugar). Participants were instructed to maintain their usual physical activity and dietary habits, and refrain from consuming flavonoid-rich foods for 24 hours before each test day.

Habitual NSS users were asked to consume at least 710 mL per day of water (control) or NSS beverage per day. Part of a behavioural weight management program that included 12 weeks of weight loss followed by 40 weeks of weight maintenance.

57 Annex 3. Characteristics of included studies

DESCRIPTION

DURATION

6 months	10 weeks	4 weeks
Water	Sucrose	Sucrose
Soft drink	Drink, food	Soft drink
Unspecified	Unspecified	Aspartame
18–65	20–50	20–55
Piernas: 210 (mixed) Tate: 318 (mixed)	2002: 41 (mixed) 2011: 23 (mixed)	133 (female)
Overweight	Overweight	Lean
Parallel	Parallel	Parallel
2008	–	–
United States	Denmark	United Kingdom

COMPARA- TOR(S)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

DESIGN

STUDY START (YEAR)

COUNTRY

STUDY

Piernas 2013
(CHOICE) (176)

Tate 2012
(CHOICE) (46)

Raben 2002 (41)8
Raben 2011 (96)

Reid 2007 (44)

Habitual consumers of SSBs were instructed to replace ≥2 servings per day (≥200 kcal) of caloric-sweetened beverages with water or NSS-sweetened beverages. Provision of 4 servings of 340–454 mL/day. NSS- sweetened beverages included still and carbonated beverages (e.g. diet versions of Coke and Sprite [Coca-Cola Company]; Pepsi, Mountain Dew, Aquafina Splash Water [PepsiCo]; Dr Pepper [Dr Pepper Snapple Group]; Diet Lipton Tea [Unilever], Nestea [Nestlé] and low-calorie fruit drinks that contain low-calorie sweeteners (e.g. Tropicana Lemonade [PepsiCo]).

Provision of 1) supplemental drinks and foods containing sucrose (~2 g/kg per day, 125–175 g/day), or 2) similar drinks and foods containing artificial sweeteners (~7 mg/kg per day, 0.48–0.67 g/day). The percentage contributions of the different artificial sweeteners were 54% from aspartame, 22% from acesulfame K, 23% from cyclamate, and 1% from saccharin. Beverages included soft drinks and flavoured fruit juices. Foods included yoghurt, marmalade, ice-cream and stewed fruits. Subjects were not informed about the true purpose of the study, but were all told that they would receive supplements containing artificial sweeteners, some of which would be newly developed.

Provision of sucrose- or aspartame-sweetened drinks (4 × 250 mL/day). Participants were informed that they were receiving either sugary drinks or “diet” drinks, meaning that half were correctly informed about the drink content and half were misinformed. Participants were recruited according to whether they were or were not currently watching their weight.

58 Health effects of the use of non-sugar sweeteners

DESCRIPTION

DURATION

4 weeks	4 weeks	14 days	6 weeks (1 week washout before start)	2 weeks	20 days	12 weeks
Sucrose	Sucrose	No inter- vention	Sucrose	Placebo, lactisole, or saccharin with lactisole	Sucrose, placebo	No inter- vention
Soft drink	Soft drink	Tabletop	Drink, food	Capsule	Soft drink, capsule	Tabletop
Aspartame	Aspartame	Sucralose	Sucralose, steviol glycosides	Saccharin	Aspartame	Stevia
20–55	20–55	18–55	18–30	18–45	18–35	18–40
53 (female)	41 (female)	66 (mixed)	42 (mixed)	54 (mixed)	48 (mixed)	28 (mixed)
Overweight	Obese	Lean	Lean	Lean	Mixed	Lean
Parallel	Parallel	Parallel	Parallel	Parallel	Crossover	Parallel
–	–	2015	–	2017	–	2019
United Kingdom	United Kingdom	Mexico	Mexico	United States	United States	United Kingdom

COMPARA- TOR(S)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

DESIGN

STUDY START (YEAR)

COUNTRY

STUDY

Reid 2010 (42)

Reid 2014 (43)

Romo-Romo 2018
(45)9

Sánchez-Delgado
2021 (271)

Serrano 2021

(272)

Spiers 1998 (184)

Stamataki 2020
(52)10

Provision of sucrose- or aspartame-sweetened drinks (4 × 250 mL/day).

Provision of sucrose- or aspartame-sweetened drinks (4 × 250 mL/day). All participants believed they received sucrose-sweetened beverages.

Intervention arm received 3× sachets (Splenda, each containing 12 mg sucralose, 958 mg dextrose and 30 mg maltodextrin) added to beverages at meals. Control did not receive sachets. Both arms were instructed to maintain their habitual food intake and physical activity.

Provision of 1) sucrose (40 g/day,) 2) sucralose (48 mg/day), or 3) steviol glycoside (100 mg/ day). Participants were directed to add the corresponding sweeteners to unsweetened beverages or food of their choice, every day, maintaining a supplementation diary and using a nutrition guide. They also received a permanent recommendation to restrict consumption of added sugars and non-caloric sweetener.

Participants were randomized to placebo, saccharin, lactisole (an inhibitor of the sweet- taste receptor), or saccharin with lactisole, administered in capsules twice daily to achieve the maximum ADI for 2 weeks.

Provision of sodas and capsules with 1) aspartame (15 mg/kg per day), 2) sucrose (90 g/day), or 3) placebo (unsweetened sodas and capsules with microcrystalline cellulose and silicon dioxide).

The intervention arm consumed 5 stevia drops (2× per day) in habitually consumed drinks. The control arm did not change their diet.

59 Annex 3. Characteristics of included studies

DESCRIPTION

DURATION

CHILDREN

3 and 6 months

12 weeks

4 weeks

2 weeks

6 weeks

18 months

Unsweet- ened beverages, SSBs and non-ca- loric sweetened bever- ages (no change)

Water

Placebo (cellulose)

Placebo (hydroxy- propyl methylcel- lulose)

Sugar

Sucrose

Drink

Capsule

Food

Soft drink

Unspecified

Advantame

Sucralose + acesulfame K

Stevia

Sucralose + acesulfame K

18–30

19–27

18–55

18–75

6–9

5–11

148 (mixed)

45 (mixed)

24 (mixed)

27 (mixed)

264 (mixed)

2012: 641
(mixed)
2013: 203
(mixed)

Lean

Overweight

Mixed

Parallel

2012

2017

–

2009

Mexico

Latvia

Australia

Italy

Nether-
lands

COMPARA- TOR(S)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

DESIGN

STUDY START (YEAR)

COUNTRY

STUDY

Vázquez-Durán11
2016 (50)

Viveros-Watty
2021 (25)

Warrington 2011

(97)

Young 2017 (273)

Cocco 2019 (209)

de Ruyter 2012
(DRINK) (274)
de Ruyter 2013
(DRINK) (275)

3 arms: 1) no sweetened beverages were permitted; only plain water, lemon and hibiscus-flavoured water, coffee and tea without sugars were permitted; 2) only beverages with non-caloric sweeteners, plain water, lemon and hibiscus-flavoured water, coffee and tea without sugars were permitted; 3) no modification in consumption of beverages, and only general recommendations given about beverages. All arms were given individualized isocaloric diets monitored via a 24-hour record of consumption and frequency of meals.

Habitual consumers of NSS-sweetened beverages were split into 2 arms: one continued consuming NSS-sweetened beverages, and the other was instructed to stop consuming.

Provision of capsules (3× per day) containing 10 mg advantame or cellulose.

Provision of capsules (3× per day) with sucralose (92 mg/day total) and acesulfame K (52 mg/day total) or placebo.

Provision of snacks (2× per day) containing stevia, maltitol or sugar. Instructions to make no changes in dietary and oral hygiene habits, and to use a fluoridated toothpaste during the experimental period.

Replacement of SSBs with artificially sweetened beverages. Provision of sucralose- sweetened (34 mg per day) plus acesulfame K– sweetened (12 mg/day) or sucrose-sweetened (26 g/day) noncarbonated beverage (250 mL/ day).

60 Health effects of the use of non-sugar sweeteners

DESCRIPTION

DURATION

MIXED (ADULTS AND CHILDREN)

8.5 months

6 months

13 weeks

Sucrose

Placebo

Lactose

Drink

Mouth rinse

Capsule

Sucralose

Stevia

Aspartame

6 –11

12–15

10 –21

398 (mixed)

108 (female)

59 (mixed)

Mixed

Overweight

Parallel

2010

2014

–

South Africa

India

United
States

COMPARA- TOR(S)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

DESIGN

STUDY START (YEAR)

COUNTRY

STUDY

Taljaard 2013 (BeForMi study) (190)

Vandana 2017

(210)

Knopp 1976 (76)

Provision of drinks (200 mL/day, 5× per week) with 1) micronutrients and sucrose (20.6 g/ day total), 2) sucrose (20.6 g/day total), 3) micronutrients and sucralose (25 mg/day total), or 4) sucralose (25 mg/day total). We compared the sugars and sucralose arms.

Daily mouth rinse with 10% stevia or placebo.

Provision of 3× 300 mg gelatin capsules 3× per day with aspartame (equivalent to 2.7 g per day) or a lactose placebo. Instructions were given for an individualized calorie-restricted diet.

–: study did not provide data; ADI: Acceptable daily intake; NSS: non-sugar sweeteners; PABA: para-aminobenzoic acid; SSB: sugar-sweetened beverage.

1 Campos et al. (2015) is a peer-reviewed publication containing more detailed data than originally reported in the abstract Campos et al. (2015) (276). Campos et al. (2017) (277) is a substudy of Campos et al.

(2015).
2 Dalenberg et al. (2020) consisted of two separate studies: one in adults and one in adolescents. The study in adolescents was halted prematurely based on results of the study in adults.
3 Ebbeling et al. (2020) is a peer-reviewed publication containing more detailed data than originally reported in the abstract Ebbeling et al. (2019) (28).
4 Engel et al. (2018) provides data for all participants of a trial originally reported in Maersk et al. (2012) (183), which was missing data from some participants. Therefore, only data from Engel et al. (2018) are

included in the meta-analyses in this review. In addition, a correction was issued in 2020 (24), as standard deviations were reported in the original publication instead of standard errors, and the corrected values

have been used in this review.
5 Fantino et al. (2018) is a peer-reviewed publication containing more detailed data than originally reported in the abstract Fantino et al. (2017) (278).
6 Madjd et al. (2018) reported data for 12 months of weight maintenance following 6 months of weight loss. Data for the 6-month weight loss period are reported in Madjd et al. (2015) (279).
7 Peters et al. (2016) reported data for 40 weeks of weight maintenance following 12 weeks of weight loss. Data for the 12-week weight loss period are reported in Peters et al. (2014) (280).
8 Raben et al. (2002) is a peer-reviewed publication containing more detailed data than originally reported in the abstract Raben et al. (2001) (281). Sorenson et al. (2014) is a substudy of Raben et al. (2002)

assessing outcomes that are not outcomes of interest (282).
9 A subsequent publication in 2020 (283) reported the same data for a slightly smaller sample size and with less detail. Therefore, data from Romo-Romo et al. (2018) were retained in the systematic review.
10 Stamataki et al. (2020) is a peer-reviewed publication containing more detailed data than originally reported in the abstract Stamataki, Crooks & McLaughlin (2020) (284).
11 Vázquez-Durán et al. (2016) is a peer-reviewed publication containing more detailed data than originally reported in the abstract Vázquez-Durán et al. (2013) (285).

Note: Blue font indicates that the study received industry funding.

61 Annex 3. Characteristics of included studies

DESCRIPTION

FOLLOW- UP (YEARS)

6 months	7	1	7	19	28	22	2–4	5
Decreased SSB with increased NSS consumption	>2/day vs 0/day	≥1/day vs <1/week	Median 817 mL/day vs none	>1/day vs <1/month	≥1/day vs none		Per serving	>7.9 mL/day vs 0–2.7 mL/day (male) >11.6 mL/day vs 0–4.6 mL/day (female)
Drink, food	Drink	Soft drink	Soft drink	Soft drink	Soft drink		Soft drink	Drink
Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified		Unspecified	Unspecified
≥18	40–69	18–75	50–71 (baseline)	53–55 (mean)	30–55 (baseline)	40–75 (baseline)	41 (mean)	18–72
101 (mixed)	198 285 (mixed)	941 (mixed)	487 922 (mixed)	35 109 (mixed)	84 085 (female)	43 371 (male)	7194 (mixed)	101 257 (mixed)
Mixed	Mixed	Over- weight/ obese	Mixed	Mixed	Mixed		Mixed	Mixed
2012	2007	2015	1995	1990	1980	1986	1999	2009
United States	United Kingdom	Germany, Netherlands, Spain, United Kingdom	United States	Australia	United States		Spain	France

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

ADULTS

Table A3.2 Prospective cohort studies

Acero 2020
(Talking Health)
(68)

Anderson 2020
(UK Biobank) (69)

Angeles
Pérez-Ara 2020
(MooDFOOD)
(187)

Bao 2008 (NIH-
AARP Diet and
Health Study)
(163)

Bassett 2020
(MCCS) (169)1

Bernstein 2012

(113)

NHS

HPFS
Bes-Rastrollo

2006 (SUN) (79)

Chazelas 2019
(NutriNet-Santé)
(164)

Effectiveness trial of 6 months to reduce SSB consumption. The data were analysed as for a cohort study, comparing participants who decreased or increased their SSB and NSS intake. 24-hour recalls at baseline and after 6 months were used to estimate NSS intake from food and drinks. A participant was considered a consumer if they consumed the equivalent of 1 oz diet soda from foods or beverages.

24-hour recall questionnaire to assess ASBs on 5 occasions.

Trial comparing the effect of different supplements on depression. Data were analysed as for a cohort. FFQ at baseline and after 12 months to estimate intake of carbonated/soft drinks with NSS.

FFQ on diet soft drink intake over past 12 months at baseline.

FFQ at baseline on consumption of diet (artificially sweetened) soft drinks.

FFQ with low-calorie (diet or artificially sweetened) sodas; included low-calorie cola with caffeine (e.g. Diet Coke, Tab with caffeine), low- calorie cola without caffeine (e.g. Pepsi Free) and other low-calorie carbonated beverages (e.g. Diet 7-Up, Fresca, Diet Mountain Dew, diet ginger ale).

Semi-quantitative FFQ.

ASBs included beverages containing non-nutritive sweeteners, such as diet soft drinks, sugar-free syrups, and diet milk-based beverages.

62 Health effects of the use of non-sugar sweeteners

DESCRIPTION

FOLLOW- UP (YEARS)

20–22

2 783 210 person years

176.7 mL/day vs 0 mL/day

User vs non-user

≥1/day vs <1/month

4.5/week–18/day vs none

Increase >0.5 serving/day vs no change (and decrease >0.5 serving/day vs no change)

User vs non-user

>603 mL/week vs 0 mL/week

Always or almost always vs never or rarely

Drink

Drink, food

Soft drink, fruit drink

Drink

Soft drink, fruit drink

Tabletop

Unspecified

18–72

≥20

30–55 (baseline)

25–42 (baseline)

40–76 (baseline)

40–75 (baseline)

30–55 (baseline)

25–42 (baseline)

40–75
(baseline)

18–30
(baseline)

43–86

104 760 (mixed)

1454 (mixed)

232 (mixed)

88 540 (female)

97 991 (male)

37 360 (male)

42 833 (male)

76 531
(female)

81 597
(female)

34 224
(male)

4161
(mixed)

66 118
(female)

61 440
(female)

Mixed

2009

1984

1980

1991

1986

1991

1986

1985

1993

France

United States

United
States

France

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Chazelas 2020 (NutriNet-Santé) (110)

Chia 2016 (BLSA)

(60)

Chia 2018 (BLSA)

(98)

Cohen 2012
(115)2

NHS
NHS II

HPFS
de Koning 2012

(HPFS) (111)

Drouin-Chartier
2019 (84)3

NHS
NHS II

HPFS
Duffey 2012

(CARDIA) (61)
Fagherazzi 2013

(E3N) (86)

Fagherazzi 2017
(E3N) (85)

24-hour dietary records every 6 months. ASBs were defined as any beverages containing NSS.

7-day dietary record of food or drink containing low-calorie sweetener (aspartame, saccharin, acesulfame potassium or sucralose).

FFQ every 4 years. ASBs included on the questionnaire were artificially sweetened cola, caffeine-free cola, non-cola, fruit punch or other fruit drink.

FFQ every 4 years. ASBs were defined as caffeinated, caffeine-free and noncarbonated low-calorie beverages.

FFQ every 4 years with low-calorie beverages with or without caffeine.

Validated questionnaire on general dietary practices and typical intake of foods during past month, assessed at baseline and years 7 and 20. Diet beverages.

Validated diet history questionnaire. Quantities were estimated by using a photo booklet. Artificially sweetened fruit drinks or soda.

Diet history questionnaire at baseline. Question: “Do you usually use artificial sweeteners, either in packets or tablets (for coffee, tea, etc.)?”

63 Annex 3. Characteristics of included studies

DESCRIPTION

FOLLOW- UP (YEARS)

11.5 (median)		3	7–8	9	24	10	11
>3/week vs non-user		>5/week vs <1/week	User vs non-user and >21/week vs none	≥1/day vs none and any vs none	≥2/day vs <1/month	≥1/day vs <1/month	>6/week vs <1/ month
Drink		Soft drink	Drink, tabletop	Soft drink	Soft drink	Soft drink	Soft drink
Unspecified		Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified
30–55 (baseline)	25–42 (baseline)	55–80	25–64 (baseline)	≥65 (baseline)	34–59 (baseline)	≥40 (baseline)	≥40 (baseline)
8863 (female)		1868 (mixed)	5158 (mixed)	5158 (mixed)	88 520 (female)	2564 (mixed)	2019 (mixed)
Mixed		Mixed	Mixed	Mixed	Mixed	Mixed	Mixed
1986	1991	2003	1979	1992	1980	1993	1993
United States		Spain	United States	United States	United States	United States	United States

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Farvid 2021 (106) NHS

NHS II

Ferreira-Pego
2016 (PREDIMED)
(62)

Fowler 2008
(SALSA) (63)

Fowler 2015
(SALSA) (64)

Fung 2009 (NHS)

(112)

Gardener 2012
(NOMAS) (108)4

Gardener 2018
(NOMAS) (87)

Women completed a validated FFQ every 4 years after diagnosis of breast cancer and were followed until death or the end of follow-up (2014 for the NHS and 2015 for the NHS II).

Semi-quantitative FFQ at baseline and yearly after. Artificially sweetened soft drinks.

Participants reporting soft drink use were asked whether they usually drank sugar-free sodas, regular sodas or similar amounts of each; their artificially sweetened soda dose was calculated accordingly. For abstainers, artificially sweetened soda dose was set equal to zero. “Usual” sweeteners for coffee and tea were ascertained, and artificial sweetener dosage was calculated accordingly (or set equal to zero for abstainers). Participants were also asked whether they “usually” used sugars or sugar substitutes. Artificially sweetened soda, coffee and tea intakes were summed to estimate ASB consumption. In cohort 1 only, baseline 24-hour dietary recalls were performed. In cohort 2 only, follow-up use of artificial sweetener (present or absent) was ascertained.

Question: “How many bottles or cans of sugar- free soft drinks do you drink per week?”

Semi-quantitative FFQ on diet over the past year, at baseline and at follow-up every 4 years. ASBs consisted of all types of low-calorie, sweet, carbonated beverages, such as diet colas and other diet carbonated beverages.

Semi-quantitative FFQ on diet over past year at baseline. Diet soda.

64 Health effects of the use of non-sugar sweeteners

DESCRIPTION

FOLLOW- UP (YEARS)

4	13	10	12.5	30	13	8
≥1/day vs none	Dose–response	Drinkers vs non- drinkers ≥4/day vs none	>1/day vs <1/month	≥2/day vs none	≥1/day vs <1/month	≥2/day vs <3/month	≥2/day vs <1/week
Soft drink	Soft drink	Soft drink, drink, tab- letop	Soft drink	Soft drink, fruit drink	Soft drink	Drink	Drink
Unspecified	Unspecified	Aspartame, saccharin, unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified
45–69 (baseline)	53 (mean baseline)	50–71 (baseline)	Varied	18–30 (baseline)	40–69	50–79 (baseline)	25–42 (baseline)
5205 (mixed)	13 697 (mixed)	263 923 (mixed)	6730 (mixed)	4719 (mixed)	35 593 (mixed)	64 850 (female)	95 464 (female)
Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed
2002	1990	1995	1991	1985	1990	1996	1991
Russia5	Australia	United States	United States	United States	Australia	United States	United States

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Garduno-Alanis 2020 (HAPIEE) (65)

Gearon 2014
(MCCS) (78)

Guo 2014 (NIH-
AARP Diet and
Health Study)
(185)

Haslam 2020
(FOS) (116)

Hirahatake 2019
(CARDIA) (88)

Hodge 2018
(MCCS) (165)

Huang 2017
(WHI-OS) (89)

Hur 2021 (NHS II)

(170)

FFQ on diet over past 3 months with artificially sweetened soft drinks. One portion was 200 mL. Categories of intake: never drinkers, occasional drinkers (<1 drink per day) and daily drinkers (≥1 drinks per day).

Diet soft drinks.

FFQ on diet over past 12 months at baseline. Diet soft drink, diet fruit drinks, diet iced tea, aspartame or Equal, saccharin or Sweet’N Low.

FFQ. Low-calorie sweetened beverages included low-calorie cola, low-calorie caffeine-free cola, and other low-calorie carbonated beverages.

Validated diet history questionnaire at baseline and years 7 and 20 on general dietary practices and typical intake of foods over previous month. ASBs were soft drinks and fruit drinks sweetened with non-nutritive (non-caloric) sweeteners.

FFQ on diet over past year, with diet (artificially sweetened) soft drinks.

FFQ at baseline, about intake of ASBs over past 3 months. “During the past 3 months, how often did you drink these beverages?” (Beverages refer to diet drinks such as Diet Coke or diet fruit drinks, with a 355 mL can as a reference size.)

Assessed SSB consumption via validated FFQs every 4 years. Modelled effect on colorectal cancer risk of replacing each serving per day of adulthood SSB intake with that of ASBs, coffee, reduced-fat milk or total milk.

65 Annex 3. Characteristics of included studies

DESCRIPTION

FOLLOW- UP (YEARS)

16	8	8	4	5	11
≥1/day vs <1/month	≥7/week vs none (beverages) Always vs none (tabletop)	Per daily serving	≥1/day vs <1/week	≥100, 400 or 600 mg/day vs none	≥2/day vs <1/month
Soft drink	Soft drink, tabletop	Drink	Soft drink	Drink	Soft drink
Unspecified	Unspecified, saccharin, sucralose, aspartame	Unspecified	Unspecified	Aspartame	Unspecified
35–79 (baseline)	42 (mean)	≥35	18–60 (baseline)	50–71 (baseline)	≥42
27 058 (mixed)	1359 (mixed)	284 345 (mixed)	2132 (mixed)	473 984 (mixed)	3318 (female)
Mixed	Mixed	Mixed	Mixed	Mixed	Mixed
1991	2007	Varied	2008	1995	1989
Denmark, France, Greece, Germany, Italy, Netherlands, Norway, Spain, Sweden, United Kingdom	United States	United States	Spain	United States	United States

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

InterAct-
Consortium 2013 (EPIC-InterAct)
(94)

Jensen 2020
(SHFS) (90)

Keller 2020 (HPP)
(118)6

Lana 2015
(ENRICA) (186)

Lim 2006 (NIH-
AARP Diet and
Health Study)
(166)

Lin 2011 (NHS)

(173)

Dietary questionnaire of intake over past 12 months at baseline with artificially sweetened soft drinks, including carbonated/soft/isotonic drinks and diluted syrups. A serving of soft drink was defined as 330 mL.

Questions: (1) How often do you drink diet drinks, like diet Coke, in the past week (never, once a week, twice a week, 3–4 times a week, 5–6 times a week, every day, more than once a day)? (2) How often do you use artificial sweeteners to sweeten your drinks (never, occasionally, often, always)? (3) If you ever use artificial sweeteners, what type do you use (saccharin, sucralose, aspartame, other – identified by brand name and colour of packet: Sweet N’ Low [pink packet], Splenda [yellow packet], Equal [blue packet], NutraSweet [white packet], or Sunett [purple packet])?

FFQ at baseline. ASBs included any diet drinks sweetened with artificial sweeteners.

Diet history at baseline. ASBs included diet or light soft drinks.

FFQ on diet over past 12 months at baseline. Diet soft drink, diet fruit drinks, diet iced tea, aspartame added to coffee or tea.

Biennial FFQ. Participants were asked to report the number of servings (“one glass, bottle or can”) consumed on average over the past year for low-calorie sugar-free carbonated beverages with or without caffeine.

66 Health effects of the use of non-sugar sweeteners

DESCRIPTION

FOLLOW- UP (YEARS)

6	34	28	10	12
≥1/day vs <1/month	≥2/day vs <1/month		≥1 can/day vs none (beverage) 145 mg/day vs 0 mg/ day (tabletop)	≥2/day vs <1/week
Soft drink	Drink		Soft drink, tabletop	Drink
Unspecified	Unspecified		Unspecified, aspartame	Unspecified
35–72 (baseline)	30–55 (baseline)	40–75 (baseline)	47–95	50–79 (baseline)
1003 (mixed)	80 647 (female)	37 716 (male)	100 442 (mixed)	81 714 (female)
Mixed	Mixed		Mixed	Mixed
2002	1980	1986	1999	1996
United States	United States		United States	United States

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Ma 2016 (FHS 3rd Generation) (55)

Malik 2019 (102)
NHS

HPFS

McCullough 2014
(CPS-II) (167)

Mossavar-
Rahmani 2019
(WHI-OS) (103)

Semi-quantitative FFQ at baseline. Diet soda intake was assessed using the following 3 items: (1) low-calorie cola; (2) low-calorie, caffeine- free cola; and (3) other low-calorie carbonated beverage.

Semi-quantitative FFQ at baseline. ASBs were defined as caffeinated, caffeine-free and noncarbonated low-calorie or diet beverages.

FFQ at baseline and after 4 years of consumption over past year. Mean consumption of artificially and sugar-sweetened carbonated beverages (“1 glass, bottle, or can [355 mL]”) during the past year was queried with use of frequency categories ranging from “never” to “≥4 per day”. Beverages types were divided into cola with caffeine, and other carbonated beverages with or without caffeine. Participants were asked about “use of NutraSweet or Equal (1 packet) (not Sweet N Low)” (manufactured by the NutraSweet Corporation, formerly Searle and Co.). Frequency responses ranged from “never” to “≥6 per day”. Total aspartame intake was calculated with use of the following values: 180 mg aspartame/355 mL (1 serving) of low-calorie cola with caffeine, 90 mg/355 mL of other low-calorie soda with caffeine, 70 mg/355 mL of other low-calorie soda without caffeine, and 20 mg aspartame per packet of NutraSweet or Equal reported, as used previously.

67 Annex 3. Characteristics of included studies

DESCRIPTION

FOLLOW- UP (YEARS)

16	6	5	11	23	4	6	4
≥2/day vs <1/month	Per daily serving	≥1/day vs rare/none	169–5848 mL/day vs non-user	>1 can/week vs none	≥1/day vs <1/month	<1/month vs ≥1/ week	0.1–28.2 g/day vs 0 g/day
Soft drink	Soft drink	Soft drink	Drink	Soft drink	Soft drink	Soft drink	Unclear
Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Saccharin
50.8 (mean)	55+	45–84 (baseline)	40–79 (baseline)	44–101 (baseline)	21–69 (baseline)	Mean 59.5 (women) Mean 45.3 (men)	18–64
477 206 (mixed)	806 (mixed)	6814 (mixed)	25 639 (mixed)	13 624 (mixed)	43 960 (female)	1636	465 (mixed)
Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed
1992	1999	2000	1993	1981	1995	2002	1986
Denmark, France, Greece, Germany, Italy, Netherlands, Norway, Spain, Sweden, United Kingdom	Spain	United States	United Kingdom	United States	United States	United States	United States

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Mullee 2019
(EPIC) (104)

Muñoz-Garcia
2019 (SUN) (188)

Nettleton 2009
(MESA) (66)

O’Connor 2015
(EPIC-Norfolk)
(91)

Paganini-Hill
2007 (Leisure
World Cohort
Study) (105)

Palmer 2008
(BWHS) (92)

Park 2020 (FHS,
FOS) (80)7

Parker 1997
(PHHP) (56)

Dietary questionnaire of intake over past 12 months at baseline. The group of soft drinks included carbonated/soft/isotonic drinks and diluted syrups, and were classified into sugar- sweetened and artificially sweetened in all centres except 3 (Italy, Spain and Sweden). A serving of soft drink was defined as 330 mL.

Semi-quantitative FFQ for year before recruitment. SSBs included carbonated colas and fruit-flavoured, carbonated, sugary soft drinks. ASBs were considered the low-calorie or artificially sweetened versions of the SSBs.

FFQ at baseline. Diet soda intake was quantified from an item listing “Diet soft drinks, unsweetened mineral water”.

7-day food diary at baseline. Intakes (g/day) were estimated for (1) soft drinks (soft drinks, squashes and juice-based drinks sweetened with sugar), (2) sweetened tea or coffee, (3) sweetened-milk beverages (e.g. milkshakes, flavoured milks, hot chocolate), (4) ASB and (5) fruit juice.

Baseline questionnaire with “How many cans or glasses per WEEK do you drink of the following – cola beverages with sugar, other soft drinks with sugar, cola beverages artificially sweetened, other soft drinks artificially sweetened?”

FFQ with diet soft drinks.

Semi-quantitative FFQ on diet soda consumption.

Semi-quantitative FFQ.

68 Health effects of the use of non-sugar sweeteners

DESCRIPTION

FOLLOW- UP (YEARS)

10	23	4 655 153 person years		5.5	20		22
≥1/day vs 0/week	>7/week vs <1/week	≥1/day vs <1/month		≥1/week vs rare/ none	>3/week vs <1/ month		Soft drink: ≥1/day vs none Tabletop: ≥129 vs 0 mg/day (male) ≥143 vs 0 mg/day (female)
Soft drink	Soft drink	Drink		Soft drink	Soft drink		Soft drink, tabletop
Unspecified	Unspecified	Unspecified		Unspecified	Unspecified		Unspecified, aspartame
45+	45–64 (baseline)	30–55 (baseline)	25–42 (baseline)	35–55 (baseline)	30–55 (baseline)	40–75 (baseline)	30–55 (baseline)	40–75 (baseline)
2888 (mixed)	15 368 (mixed)	82 713 (female)	93 085 (female)	2037 (male)	77 218 (female)	47 810 (male)	77 218 (female)	47 810 (male)
Mixed	Mixed	Mixed		Mixed	Mixed		Mixed
1971	1987	1980	1991	2003	1984	1986	1984	1986
United States	United States	United States		Japan	United States		United States

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Pase 2017 (FOS)

(114)

Rebholz 2017
(ARIC) (174)8

Romanos-
Nanclares 2021
(171)

NHS
NHS II

Sakurai 2014 (93)

Schernhammer
2005 (286)

NHS
HPFS

Schernhammer
2012 (168)

NHS

HPFS

FFQ at baseline and every 4 years. Diet beverages included low-calorie cola with caffeine, low- calorie caffeine-free cola and other low-calorie beverages.

FFQ at baseline and visit 3. Diet soda was described on the FFQ as one 237 mL glass of low- calorie soft drinks such as Diet Coke, Diet Pepsi or Diet 7-Up.

FFQ at baseline and every 4 years. Cumulatively averaged intakes of SSBs and NSS-sweetened beverages from FFQs were tested for associations with incident breast cancer cases and subtypes.

Diet history questionnaire. Diet soda consisted of non-calorie carbonated soft drinks.

FFQ at baseline and every 4 years. Diet soft drinks included low-calorie cola, low-calorie caffeine- free cola, and other low-calorie carbonated beverages.

Semi-quantitative FFQ on consumption over past year, every 4 years. The frequency of diet soda consumption was assessed per 12 fl oz (355 mL, equivalent to one bottle, glass or can) serving for the following 3 items: diet cola with caffeine, diet cola without caffeine and other diet soda. Use of aspartame sweeteners added at the table (i.e. NutraSweet and Equal [manufactured by the NutraSweet Company, formerly Searle and Co]) was initially included on the FFQ in 1994 and was assessed as individual serving packets. Total aspartame intake was calculated as the sum from diet soda and packets (20 mg). The aspartame content of each soda item on the FFQ was assigned as a weighted average of the representative sodas in that category (70–180 mg/serving).

69 Annex 3. Characteristics of included studies

DESCRIPTION

FOLLOW- UP (YEARS)

4			6	11	2
Per daily serving			User vs non-user	Per daily serving	Per daily serving Increase of >1 week vs no change
Soft drink			Soft drink, tabletop	Soft drink	Soft drink
Unspecified			Unspecified	Unspecified	Unspecified
30–55 (baseline)	25–42 (baseline)	40–76 (baseline)	50–69 (baseline)	50–60 (baseline)	25–64 (baseline)
121 701 (female)	116 683 (female)	51 530 (male)	78 694 (female)	477 206 (mixed)	11 218 (female)
Mixed			Mixed	Mixed	Mixed
1986	1991	1986	1982	1992	2006
United States			United States	Denmark, France, Greece, Germany, Italy, Netherlands, Norway, Spain, Sweden, United Kingdom	Mexico

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Smith 2015 (57)9 NHS

NHS II
HPFS

Stellman 1986
(American Cancer
Society study)
(67)10

Stepien 2016
(EPIC) (287)

Stern 2017
(Mexican
Teachers’ Cohort)
(58)

FFQ every 4 years. Diet soda intake over past year, converted into servings per day.

Question: “Do you now or have you ever added artificial sweeteners (saccharin or cyclamates) to coffee, tea, or other drinks or food?” Choices were: yes, currently, formerly, never. The next question was “If ever used artificial sweeteners, indicate amount per day and for how long”, with separate space to record packets, drops and tablets. Also asked were quantity and duration of both current and former use of diet soda and diet iced tea. The study was restricted to those who either had never used artificial sweeteners or were long-term current users, defined as those who answered “yes, currently” to the usage question and who had used packets, tablets, drops and diet beverages for at least 10 years. Former users of artificial sweetener were excluded.

Semi-quantitative FFQ. One question on sugar- free soda.

70 Health effects of the use of non-sugar sweeteners

DESCRIPTION

FOLLOW- UP (YEARS)

CHILDREN

6 –10

Up to 20

7.9

User vs non-user

≥2/day vs 0–3/ month

≥1/day vs none

≥2/day vs 0/day

Per daily serving

Soft drink

Drink

Soft drink

Unspecified

35–45

50–79 (baseline)

42–52 (baseline)

320
(baseline)

9 –16

8–12

170 (female)

59 614 (female)

1235 (female)

31 402
(mixed)

16 771
(mixed)

164 (mixed)

Mixed

–

1993

1996

1999

1996

1992

United States

United
States

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Tucker 2015 (59)

Vyas 2015 (WHI-
OS) (109)

Wang 2019
(SWAN) (117)

Zhang 2021
(NHANES) (107)

Berkey 2004
(GUTS) (191)

Blum 2005 (192)

Usual soft drink intake was assessed with a questionnaire that included 6 soft drink questions. Frequency and type of soft drinks consumed were measured using questions that focused on use of artificially sweetened soft drinks, sugar-sweetened soft drinks, beverage size, and number of soft drinks consumed per week.

FFQ at baseline, year 5 and year 9. Nineteen beverages were aggregated into 8 non- overlapping groups: coffee, tea, SSBs, ASBs, fruit juices, whole milk, milk with lower fat content (2% milk, 1% milk and skim milk), and alcoholic beverages. The intake of each group was calculated by summing the individual items in that group. To capture long-term intakes, the intake of each beverage group was calculated by averaging across up to 3 available dietary measurements (baseline, visit 5 and visit 9).

One or two 24-hour dietary recalls at baseline. ASBs were defined as sugar-free soft drinks and carbonated water. Linkage of NHANES with National Death Index using a probabilistic matching algorithm.

FFQ on diet soda. 24-hour dietary recall with diet soda.

71 Annex 3. Characteristics of included studies

DESCRIPTION

FOLLOW- UP (YEARS)

1	7	5	3	2	19	3	7	8 months	10	5
Chronic user vs never	Per daily serving	≥1/day vs 0/week	Dose–response	Per daily serving	Per daily serving	≥1/day vs <1/week	Low vs no intake	Per daily serving	Per daily serving	≥1/day vs 0/week
Drink	Soft drink	Soft drink	Soft drink	Soft drink	Soft drink	Soft drink	Soft drink	Soft drink	Soft drink	Soft drink
Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified
12–18	9 –16 (baseline)	12–16 (baseline)	3–6	15 (mean baseline)	11–13	4–8	4–7	2–5	9 –10 (baseline)	12–16 (baseline)
98 (mixed)	7559 (mixed)	2516 (mixed)	49 (mixed)	693 (mixed)	548 (mixed)	2332 (mixed)	642 (mixed)	1345 (mixed)	2371 (mixed)	2294 (mixed)
Overweight	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed
2004	2004	1998	–	2006	1995	2006	1992	1995	1987	1998
United States	United States	United States	United States	United States	United States	United Kingdom	United States	United States	United States	United States

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Davis 2018 (SOLAR) (193)

Field 2014 (GUTS
II) (194)

Haines 2012
(EAT) (195)

Kral 2008 (204)
Laska 2012 (IDEA,

ECHO) (196)
Ludwig 2001

(197)

Macintyre 2018
(GUS) (198)

Marshall 2003
(IFS) (211)

Newby 2004
(North Dakota
WIC Program for
Children) (199)

Striegel-Moore
2006 (NGHS)
(200)

Vanselow 2009
(EAT) (201)

2 × 24-hour dietary recalls at baseline and endline. ASBs included sodas, coffees, energy drinks, teas, sports drinks, juices and flavoured waters. Chronic user was defined as consuming ASBs at baseline and follow-up. Never user (control) was defined as not consuming ASBs at baseline or follow-up.

Semi-quantitative FFQ every 2 years with diet soda.

Diet soda intake assessed by Project EAT-I survey, a 221-item self-report instrument.

3-day weighted food record every year. Diet soda including carbonated non-caloric beverages.

FFQ diet over the past month. Question about “diet or sugar-free soda or pop”.

FFQ of intake over past 30 days. One question, concerning diet soda, was used to establish the intake of diet soda per day.

Exposure to ASBs was measured at age 4–5 with the question: “How often does X drink diet or low calorie soft drinks? INTERVIEWER: Include cans, bottles, mixers. Include diet or low-cal flavoured water here. Do not include fresh fruit juice or water”.

3-day food and beverage diaries at 1, 2, 3, 4 and 5 years of age. Sugar-free soda pop.

FFQ at baseline and follow-up. Diet soda included all no- or low-calorie soda.

3 consecutive-day food records at years 1, 2, 3, 4, 5, 7, 8 and 10. Diet soda included all diet carbonated beverages, excluding water.

FFQ, included low-calorie soft drinks.

72 Health effects of the use of non-sugar sweeteners

DESCRIPTION

FOLLOW- UP (YEARS)

PREGNANT WOMEN

1.5

Per daily serving

Per 100 mL/day

≥1/day vs <1/month

Drink

Soft drink, hot drink

Unspecified

7–12

2–6

14–22

32 (mean)

237 (mixed)

288 (mixed)

667 (mixed)

3033

Mixed

1997– 1999

2009

2003

2009

Australia

Denmark

Australia

Canada

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Zheng 2015a
(CAPS) (202)

Zheng 2015b
(Healthy Start
Study) (203)

Zheng 2019
(Raine) (77)

Azad 2016
(CHILD) (226)11

3× 24-hour recall at 9 years. Beverages were grouped into 6 categories: (1) water (tap, bottled and unflavoured mineral), (2) SSBs (regular soft drinks, fruit drinks, cordials and sugar- sweetened sport drinks), (3) milk (full fat, reduced fat, skim and flavoured), (4) coffee/tea (plain and sweetened), (5) 100% fruit juice (apple, blackcurrant, grape, orange and fruit blend), and (6) diet drink (low-energy drinks sweetened with artificial sweeteners).

4-day dietary record. Beverages were classified as (1) water (tap water, sparkling water and still water), (2) milk (skimmed milk, low-fat milk, whole milk, butter milk and flavoured milk), (3) sugary drinks (sugar-sweetened carbonated and fruit-flavoured drinks, and fruit juice) and (4) diet drinks (ASBs).

Semi-quantitative FFQ at baseline (14 years). Six beverage types were evaluated in the present study: (1) SSBs (carbonated soft drinks including cola, cordials or fruit drink concentrate, and fruit juice drinks with the exclusion of 100% fruit juice), (2) plain water (spring and mineral water), (3) tea and coffee (plain and sweetened), (4) diet drinks (low-calorie, artificially sweetened drinks), (5) 100% fruit juice (100% fruit and vegetable juices), and (6) milk (whole, reduced fat, skim, dairy and soy milk).

FFQ in 2nd–3rd trimester. Intake of NSS- sweetened beverages was determined from reported consumption of diet soft drinks or pop (1 serving = 355 mL) and artificial sweetener added to tea or coffee (1 serving = 1 packet).

73 Annex 3. Characteristics of included studies

DESCRIPTION

FOLLOW- UP (YEARS)

10	7	9	9	7	9	8 months (from pregnan- cy week 6–10 to delivery) Up to 7	Up to 16	9 months
1/day vs 0–3/month	Per daily serving	≥70 mL/day vs ≤25 mL/day, ≥4/day vs none	≥70 mL/day vs ≤25 mL/day, ≥4/day vs none	Per daily serving	Per daily serving	≥4/day vs never, ≥1/ week vs <1/week	≥2/week in pregnancy and at follow-up vs ≤4/ month in pregnancy and at follow-up	Excessive, optimal and suboptimal gestational weight gain
Soft drink	Soft drink	Soft drink	Soft drink	Soft drink	Soft drink	Soft drink	Soft drink, hot drink	Drink
Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified
31–32 (mean)	32 (mean baseline)	30 (mean)	30 (mean)	32 (mean baseline)	18–43	29 (mean)	31–32 (mean)	30 (mean)
1347	1234	88 514	60 761	1078	2286	59 334	607	1326
Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed
1991	1999	1999	1999	1999	201312	1996	1996	2015
United States	United States	Norway	Norway	United States	Germany	Denmark	Denmark	Iceland

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Chen 2009 (NHS II) (217)

Cohen 2018
(Project Viva)
(215)

Dale 2019 (MoBa)

(230)

Englund-Ögge
2012 (MoBa)
(220)

Gillman 2017
(Project Viva)
(227)

Gunther 2019
(GeliS) (223)

Halldorsson 2010
(Danish National
Birth Cohort)
(221)

Hinkle 2019
(DWH) (235)

Hrolfsdottir 2019
(PREWICE) (234)

Semi-quantitative FFQ about intake over past year. Pre-pregnancy diet beverage consumption. Diet beverages included low-calorie cola with caffeine, low-calorie caffeine-free cola, and other low-calorie beverages.

Self-administered semi-quantitative FFQ during 1st and 2nd trimester of pregnancy and mid- childhood.

Semi-quantitative FFQ (2×) in pregnancy with artificially sweetened soft drink.

Self-administered, semi-quantitative FFQ during 1st and 2nd trimesters of pregnancy and mid- childhood.

FFQ during early and late pregnancy. Light drinks included low- or non-caloric sweetened beverages.

FFQ at ~25 weeks of pregnancy for intake over past month. Artificially sweetened carbonated and non-carbonated soft drink.

FFQ at ~25 weeks of pregnancy for intake over past month, and FFQ 9–16 years later. ASBs with or without coffee and tea with added artificial sweeteners.

FFQ during first trimester, with ASBs.

74 Health effects of the use of non-sugar sweeteners

DESCRIPTION

FOLLOW- UP (YEARS)

8 months (from pregnan- cy week 6–10 to delivery) Up to 7	9 months	9 months	9 months	13 months	10	Up to 7
≥4/day vs never, ≥1/ week vs <1/week	Linear	>4/day vs 0/day	≥1/day vs 0/day	Per 10 g of ASBs standardized to 1000 kcal/day	≥4/day vs none	≥1/day vs never
Soft drink	Drink	Soft drink	Soft drink	Drink, food	Drink	Soft drink
Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified	Unspecified
21–39	22–42	26 –27 (mean)	31 (mean)	29 (mean)	–	31 (mean)
60 466	57	8914	342	1698	66 387	918
Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed
1996	2017	2007	2009	200613	1996	1996
Denmark	Slovenia	United Kingdom	Denmark	Netherlands	Denmark	Denmark

COMPARISON (SERVINGS-HIGHEST VS LOWEST)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

PARTICIPANT WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Maslova 2013 (Danish National Birth Cohort)
(229)

Munda 2019

(225)

Petherick 2014
(BiB) (222)

Renault 2015
(TOP study) (233)

Salavati 2020
(Perined-
Lifelines Cohort)
(224)

Schmidt 2020
(Danish National
Birth Cohort)
(231)

Zhu 2017 (DWH)

(228)

FFQ at ~25 weeks of pregnancy for intake over past month. Artificially sweetened carbonated and non-carbonated soft drink.

FFQ before and during pregnancy.

Questionnaire on intake of artificially sweetened cola over past 4 weeks. Consumption was categorized as 0, 1, 2, 3 or ≥4 cups per day, with each cup measuring 200 mL.

FFQ at beginning (weeks 11–14) and end (weeks 36–37) of pregnancy. Artificially sweetened carbonated soft drinks.

FFQ with artificially sweetened products.

FFQ at 25 weeks of pregnancy. Intakes of artificially sweetened carbonated and uncarbonated drinks.

FFQ at ~25 weeks of pregnancy for intake over past month and for a subsample; also at 33–35 weeks of pregnancy

–: study did not provide data; ADI: acceptable daily intake; ASB: artificially sweetened beverage; FFQ: food frequency questionnaire; NSS: non-sugar sweeteners; SSB: sugar-sweetened beverage.

1 Bassett et al. (2020) is the published version of Bassett et al. (2019) (172), which is a preprint.
2 Cohen et al. (2012) updates the results (i.e. reports on additional follow-up from baseline) of a previous report on hypertension in two of these cohorts: Winkelmayer et al. (2005) (288).
3 Drouin-Chartier et al. (2019) updates the results (i.e. reports on additional follow-up from baseline) of previous reports on type 2 diabetes in these cohorts: Schulze et al. (2004) (289), de Koning et al. (2011)

(290) and Bhupathiraju et al. (2013) (291).
4 Gardener et al. (2012) is a peer-reviewed publication containing more detailed data than originally reported in the abstract Gardener et al. (2011) (292).
5 Study includes body mass index data from Russia, Poland and Czech Republic, but the data are only provided longitudinally for Russia.
6 Pooling study not included in meta-analyses but reported narratively. Includes Atherosclerosis Risk in Communities Study (ARIC), Alpha-Tocopherol and Beta-Carotene Cancer Prevention Study (ATBC), Health

Professionals Follow-up Study (HPFS), Iowa Women’s Health Study (IWHS), Women’s Health Study (WHS) and Nurses’ Health Study (NHS).
7 Park et al. (2020) is a prospective cohort study assessing the same population assessed cross-sectionally in Ma et al. (2015) (293).

75 Annex 3. Characteristics of included studies

DESCRIPTION

ADULTS

COMPARISON

User vs non- user	Ever vs never	Ever vs never	User vs non- user	User vs non- user	≥1/week vs <1/week	User vs non- user	≥1/day vs 0/ day	Ever vs never
Tabletop	Tabletop	Tabletop	Tabletop	Soft drink, tabletop, wine	Tabletop	Tabletop	Soft drink	Tabletop
Unspecified	Unspecified, saccharin/cyclamate, aspartame/ acesulfame K	Unspecified	Unspecified, saccharin	Unspecified, saccharin	Aspartame	Saccharin	Unspecified	Unspecified
24–80	–	–	22–80	<90	20–86	–	21–85	–
388 (mixed)	594 (mixed)	964 (mixed)	3117 (mixed)	812 (mixed)	244 (mixed)	1901 (mixed)	2233 (mixed)	1044 (mixed)
Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed
1980	1999	1981	1991	1978	2005	–	1995	–
Turkey	Argentina	United States	Italy	Spain	France	United Kingdom	United States	Canada

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

8 Rebholz et al. (2017) updates the results (i.e. reports on additional follow-up from baseline) of a previous report on chronic kidney disease in this cohort: Bomback et al. (2010) (294).
9 Smith et al. (2015) updates the results (i.e. reports on additional follow-up from baseline) of previous reports on body weight in these cohorts: Colditz et al. (1990) (295), Schulze et al. (2004) (289), Mozaffarian

et al. (2011) (296) and Pan et al. (2013) (297).
10 A subsequent analysis of the dietary quality of the participants in this cohort was conducted but provided no new information on outcomes of interest: Stellman et al. (1988) (298).
11 A subsequent publication in 2020 (250) reported the same data but with less detail. Therefore, data from Azad et al. (2016) were retained in the systematic review.
12 This study is a secondary cohort analysis of the GeliS (“healthy living in pregnancy”) RCT, which was initiated in 2013 and completed in 2018.
13 The Perined-Lifelines linked birth cohort was created by linking two existing databases: a large population-based cohort study (The Lifelines Cohort study, which enrolled participants beginning in 2006) and

the Dutch national birth registry (Perined).

Table A3.3 Case–control studies reporting on cancer

Akdaş 1990

(119)

Andreatta
2008 (120)

Asal 1988

(121)

Bosetti 2009

(122)

Bravo 1987
(123, 124)

Cabaniols
2011 (125)

Cartwright
1981 (126)

Chan 2009

(127)

Connolly
1978 (128)

Interview asking about “use of artificial sweeteners”.

Dietary recall of habitual use of artificial sweeteners over past 5 years. Artificial sweeteners were classified into saccharin/cyclamate and aspartame/acesulfame K.

Question on ever use of artificial sweeteners or sugar substitutes.

FFQ, usual diet 2 years before diagnosis, users vs non-users. FFQ included specific questions on weekly consumption of saccharin and other low-calorie sweeteners (mainly aspartame) expressed in sachets or tablets.

Users vs non-users of artificial sweetener (saccharin) and artificially sweetened beverages (wine and sodas)

FFQ over past 5 years, non-consumers (<1 per week) and regular consumers (≥1 per week) of aspartame sweetener.

Questionnaire on saccharin use.

Sugar-free carbonated beverages included low-calorie colas, low-calorie caffeine-free colas, and other low-calorie carbonated beverages, such as Diet 7-Up, Fresca and diet ginger ale.

Question: “Do or did you use artificial sweeteners?”

76 Health effects of the use of non-sugar sweeteners

DESCRIPTION

COMPARISON

User vs non- user	>2/day vs 0/ day	Ever vs never	User vs non- user	User vs non- user	Ever vs never	Ever vs never	User vs non- user	2/day vs 0/ day	Always vs never
Hot drink	Tabletop	Soft drink, tabletop	Drink, tabletop	Drink	Drink, food, tabletop	Drink, food, tabletop	Unclear	Drink, food, tabletop	Tabletop
Unspecified	Undefined, saccharin	Unspecified	Unspecified, saccharin	Aspartame	Unspecified	Unspecified, saccharin	Saccharin	Unspecified, saccharin, cyclamate	Unspecified
<70	57–66 (median)	66–69 (mean)	20–80	21–80	21–84	67–69 (mean)	–	–	≥50
2822 (female)	16 004 (mixed)	603 (mixed)	534 (mixed)	699 (mixed)	8793 (mixed)	632 (mixed)	351 (mixed)	1038 (mixed)	159 (male)
Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed
1983	1991	1977	1977	1994	1977	1974	1983	1972	2002
Denmark	Italy	United States	United States	Sweden	United States	Canada	Argentina	United States	Lebanon

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Ewertz 1990

(129)

Gallus 2007

(130)

Gold 1985

(131)

Goodman
1986 (132)

Hardell 2001

(133)

Hoover 1980

(134)

Howe 1977,
1980 (135,
136)

Iscovich
1978 (299)

Kessler 1976,
1978 (138,
139)

Kobeissi
2013 (140)

Semi-quantitative FFQ 1 year after diagnosis and 1 year before diagnosis. Artificial sweeteners in coffee or tea.

FFQ about diet 2 years before diagnosis (cases) or before hospital admission (controls). FFQ included specific questions on weekly consumption of sugars (expressed in teaspoons/ week), and saccharin and other sweeteners (expressed in sachets or tablets/week).

FFQ on diet before onset of the illness with diet soda and artificial sweeteners.

User of saccharin or diet beverage was defined as consumer of 30 mg saccharin or 110 mL diet beverage per week for a period of 1 year of more.

Consumption of low-calorie drinks was asked about, including years of intake, times per day or week, and amount of drink each time, to assess the intake of aspartame.

Personal interview in home with detailed history of artificial sweetener use in 3 forms (tabletop sweetener, diet drinks and diet foods).

The following question was asked: “Do you now, or have you ever used sugar substitutes?” If yes, the number of tablets or drops usually used and the frequency and duration of using that brand were determined for each brand or type used. Other questions related to similar data for the use of diet drinks and for dietetic foods such as puddings, salad dressings and confectionery.

Interviewer-administered questionnaire, with saccharin.

Intensive personal interview on use of NSS. Use of NSS was probed for table sweeteners, diet beverages, diet foods, and total intake in all forms. For each specific NSS-containing substance, information was obtained on the frequency, quantity and duration of use by type and brand. Excluded 1 year before cancer diagnosis.

Face-to-face interview on artificial sweetener consumption before diagnosis.

77 Annex 3. Characteristics of included studies

DESCRIPTION

COMPARISON

User vs non- user	≥2/day vs never	≥15/day vs never, user vs never	≥365 in life vs <365 in life	User vs never	User vs non- user	User vs non- user
Tabletop	Soft drink	Drink, food, tabletop	Tabletop	Unclear	Soft drink, food, tabletop	Drink, tabletop
Unspecified	Unspecified	Unspecified, saccharin, cyclamate	Saccharin	Saccharin	Unspecified	Unspecified
<20 to >60 (53% were 40–60)	35–90	–	≥50	44–83	–	≥40
450 (mixed)	1138 (mixed)	1175 (mixed)	1085 (male)	141 (female)	464 (mixed)	12 736 (mixed)
Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed
2010	1982	1979	1987	1977	–	1969
Egypt	United States	Denmark	France	Denmark	Canada	Unclear (7 countries)

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Mahfouz 2014 (141)

Mettlin 1989

(142)

Møller-
Jensen 1983
(143)

Momas 1994

(144)

Mommsen
1983 (145)

Morgan 1974

(146)

Morrison
1979 (147)

Questionnaire on dietary habits 2 years before cancer diagnosis. Artificial sweetener.

Questionnaire with diet cola intake: number of glasses, cups or drinks usually drunk each day.

Detailed history questionnaire on artificial sweeteners, which included information on regular use of artificial sweeteners in coffee, tea or foods for at least 3 months. If affirmative, further information was sought on the reasons for such use, age at starting and stopping regular use, commercial brand name, amount normally used, and regular use 1 year before interview.

Questionnaire. Intake of artificial sweeteners dealt with the use of saccharin as added to food/beverages only. Consumption of saccharin from other sources (food and drink) was not considered.

Questionnaire. Saccharin.

Questionnaire with artificial sweetener intake. Users were defined by regular use for more than 1 year of diet desserts, sugar-free soft drinks or sugar substitutes.

Exposure used was the one recorded at the first monitored hospital admission. Users used artificial sweeteners or diet drinks for more than 3 years.

78 Health effects of the use of non-sugar sweeteners

DESCRIPTION

COMPARISON

Used vs never	Used vs never	User vs non- user	User vs non- user
Drink, food, tabletop	Drink, food, tabletop	Tabletop	Drink, tabletop
Unspecified	Unspecified	Unspecified	Unspecified, saccharin
21–89	21–89	21–89	67–71 (mean)
1128 (mixed)	1290 (mixed)	882 (mixed)	217 (mixed)
Mixed	Mixed	Mixed	Mixed
1976	1976	1976	1978
United States	United Kingdom	Japan	United States

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Morrison
1980 (148)

Interview on exposure history. Subjects were asked “Have you ever consumed diet or low-calorie beverages – Tab Fresca, Diet Pepsi or artificially sweetened instant tea, lemonade, punch, or fruit juice, for instance?” Those who answered “yes” were asked the average frequency of consumption during the period of use, when use began, the time period of maximum frequency, what the maximum frequency had been, current frequency, and time of discontinuation of use, if applicable. Subjects were also asked whether they had “ever used substitutes for sugars or artificial sweeteners such as Sweet’N Low, Sucaryl, saccharin or cyclamates”. Those who answered “yes” were asked when use began; the reason for use; whether they had ever used saccharin and when use of that substance began; current use; the usual brand used; the current amounts and frequencies used in coffee, tea and other beverages and foods; and, if no longer used, the time of discontinuation. All subjects were also asked current frequencies of use of “low-calorie, dietetic, or low-sugar brands of ice cream, cookies or candy, canned fruit, pudding or gelatin, jam or jelly, salad dressing or other diet or low-calorie foods”. Subjects in Japan were only asked about sugar substitutes, not dietetic beverages and foods.

Participants were asked if they consumed diet or low-calorie beverages (with examples), when use began, their average frequency of consumption during period of use, the period of maximum frequency, the current frequency and the time of discontinuation of use, if applicable. Participants were also asked if they consumed any sweetener other than sugar, when use began, whether used currently, usual brand, current amounts and frequencies of use, and time of discontinuation, if applicable. Participants were asked about the current frequency of use of low-calorie and low-sugar brands of various foods.

Participants were asked about their use of sugar substitutes added to beverages and foods.

Questionnaire on ingestion of coffee, cola beverages and saccharin.

Morrison
1982 (149)

Najem 1982

(150)

79 Annex 3. Characteristics of included studies

DESCRIPTION

COMPARISON

6+ serving years, 3+ can years vs non- user	User vs non- user	Ever vs never	User vs non- user	>4/day, >1/ day, >3/day vs 0/day	Ever vs never	User vs non- user	Number of glasses/week	≥15 years of use vs non- user	Ever, ≥15 years of use vs never	≥19/year vs 0/year	≥20/year vs <1/year
Soft drink, tabletop	Tabletop	Tabletop	Tabletop	Drink, food, tabletop	Drink, food, tabletop	Hot drink	Drink	Tabletop	Drink, tabletop	Tabletop	Tabletop
Unspecified, saccharin	Unspecified	Unspecified	Unspecified	Unspecified, saccharin, cyclamate	Unspecified	Saccharin, cyclamate	Unspecified	Unspecified	Saccharin	Saccharin	Saccharin
30–93	40–79	20–90	26–81	35–79	21–84	63 (mean)	21–85	40–80	–	≥20	22–78
783 (mixed)	400 (mixed)	882 (mixed)	260 (mixed)	1618 (mixed)	1136 (mixed)	525 (female)	251 (mixed)	315 (mixed)	782 (mixed)	471 (mixed)	240 (mixed)
Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed	Mixed
1977	1982	1976	1997	1979	1977	1965	1977	1973	1977	1987	1987
United States	Sweden	Japan	Serbia	Canada	United States	United States	United States	United States	United States	China	China

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Nomura 1991

(151)

Norell 1986

(152)

Ohno 1985

(153)

Radosavl-
jević 2001
(154)

Risch 1988

(155)

Silverman
1983 (156)

Simon 1975

(157)

Sullivan 1982

(158)

Wynder 1977

(159)

Wynder 1980

(160)

Yu 1997

(161)

Zou 1990

(162)

Diet history of usual week 1 year before diagnosis, included artificially sweetened beverages, such as diet or low-calorie sodas, and information on use and frequency of use of saccharin, cyclamates and other artificial sweeteners.

Questionnaire on past exposures, including artificial sweeteners, before illness.

Interview at home, including use of sugar substitute or artificial sweeteners.

Interview: asked when started, daily amount, kind, duration, and cessation of intake of tea and artificial sweeteners.

History questionnaire, including regular consumption of tabletop artificial sweeteners, and low-calorie foods and drinks. Reported artificial sweeteners were classified by brand name and date of use as saccharin, cyclamate or both, to estimate average daily intake and cumulative lifetime consumption of these substances.

To elicit detailed information on consumption of artificial sweeteners, the questionnaire included items on use of tabletop sweeteners, diet drinks and diet foods.

Questionnaire, including questions on coffee additives, and type and strength of coffee and decaffeinated coffee. Use of cyclamate in coffee or tea.

In-home interview, use of artificial sweeteners.

Interview. Considered only consumption of artificial sweeteners that had been on the market for several decades, not those, such as cyclamates, that were developed in the recent past.

Interview. Data on intake of coffee, tea and other beverages, including those containing artificial sweeteners.

Questions on use of saccharin. Saccharin use in times/year and number of years.

80 Health effects of the use of non-sugar sweeteners

DESCRIPTION

CHILDREN

COMPARISON

PREGNANT WOMEN AND CHILDREN

≥2/day vs <1/ month

User vs non- user

Soft drink

Drink, tabletop

Unspecified

Aspartame

0–19

630 (mixed)

150 (mixed)

Mixed

1991

1984

United States

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS (SEX)

WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STUDY

Bunin 2005

(206)

Gurney 1997

(207)

FFQ on diet during early pregnancy and mid-pregnancy, with diet soda.

Aspartame consumption during pregnancy and during childhood, before date of diagnosis, from biological mother. Questions were asked about the child’s consumption of aspartame or NutraSweet, including age at first consumption, time period of consumption and frequency of consumption, for any food, chewing gum or diet drink. Questions were also asked about the mother’s consumption of aspartame or NutraSweet, including trimesters of consumption, time period of consumption and frequency of consumption, for any food, chewing gum or diet drink during pregnancy or while breastfeeding. Subdivided into all sources and diet drinks.

–: study did not provide data; FFQ: food frequency questionnaire; NSS: non-sugar sweetener.

81 Annex 3. Characteristics of included studies

NONRANDOMIZED CONTROLLED TRIALS

ADULTS

CHILDREN

Bouchard 2010 (NHANES) (303)	de Castro 2009 (309)	Fitzgerald 2008 (315)	Hunt 2020 (321)	Marques-Vidal 2017 (CoLaus study) (326)	Shoham 2008 (NHANES) (329)	Yoshida 2007 (FOS) (335)
Bleich 2014 (NHANES) (302)	Crichton 2015 (MSLS and ORISCAV-LUX) (308)	Fernandes 2013 (314)	Hess 2018 (320)	Malek 2018 (NHANES) (325)	Pergrin Marriott 2016 (NHANES) (178)	Yarmolinsky 2016 (ELSA-Brasil) (334)
Barrett 2017 (Fenland Study) (301)	Chen 1991 (307)	Duran Aguero 2015 (313)	Hedrick 2017 (Talking Health) (319)	Mahar 2007 (182)	Perez 2021 (pregnant women) (218)	Wulaningsih 2017 (NHANES) (333)
Arrais 2019 (PNAUM) (300)	Carroll 2016 (NDNS) (306)	Drewnowski 2016 (NHANES) (312)	Hartman 2017 (HHHF) (318)	Mackenzie 2006 (NHANES) (324)	Nicolì 2021 (pregnant women) (219)	Winther 2017 (332)

Giammattei 2003 (341)

Mariscal-Arcas 2014 (345)

Souza 2016 (349)

Serra-Majem 1996 (355)

Forshee 2003 (CSFII) (340)

Ledoux 2011 (344)

Skeie 2019 (Tromso Study) (348)

Jones 2019 (CCHS-Nut) (354)

Duran Agüero 2014 (339)

Laverty 2015 (MCS) (343)

Serra Majem 1993 (213)

Grech 2018 (NNPAS) (353)

Berentzen 2015 (PIAMA) (216)

Kim 2017 (214)

Seferidi 2018 (NDNS) (347)

French 2013 (352)

MIXED (ADULTS AND CHILDREN)

CROSS-SECTIONAL STUDIES

Table A3.4 Included nonrandomized controlled trials and cross-sectional studies

Appleton 2007 (177)

Appleton 2001 (179) Brunkwall 2019 (MDCS) (305)

Deshmukh-Taskar 2009
(Bogalusa Heart Study) (311)

Gomez Roig 2017 (pregnant
women) (317)

Leahy 2017 (NHANES) (323)
Mostad 2014 (HUNT) (328)

Wensel 2019 (OPREVENT2) (331)
Yu 2018 (NHS) (337)

Beck 2014 (338)

Katzmarzyk 2016 (ISCOLE) (342)
O’Connor 2006 (NHANES) (347)

Barraj 2019 (NHANES and
WWEIA) (351)

Sylvetsky 2017 and 2019
(NHANES) (242, 357)

Hieronimus 2020 (83)1

Naismith 1995 (81)

Tordoff 1990 (82)

Wolraich 1994 (children) (205)

1
Hieronimus et al. (2020) is a more complete data set that was originally reported in Stanhope et al. (2015) (254) and Hieronimus et al. (2019) (358).

Bragg 2013 (304) den Biggelaar 2019

(Maastricht Study) (310) Geraldo 2013 (316)

Kuk 2016 (NHANES) (322) Miller 2020 (327)

Tamez 2018 (Mexican Teachers Cohort) (330)

Yu 2017 (Atlantic PATH) (336)

Hardy 2018 (NSW Schools Physical Activity and Nutrition Survey [SPANS]) (212)

Milla Tobarra 2014 (Cuenca study) (346)

Venegas Hargous 2020 (FEChiC) (350)

Silva Monteiro 2018 (Brazilian National Dietary Survey) (356)

82 Health effects of the use of non-sugar sweeteners

DESCRIPTION

ADULTS

DURATION

6 months	4 weeks	8 weeks	1 week (4 weeks run-in and washout)	2 weeks	12 weeks	2 weeks
Sugar, water	Unsweetened soft drink	High- fructose corn syrup	–	Sucrose	Water	Placebo
Drink	Soft drink	Drink	Drink	Drink	Drink	Capsule
Unspecified	Unspecified	Aspartame	Sucralose, aspartame	Stevia, saccharin	Unspecified	Saccharin
20–50	18–50	18–40	18–45	40–70	18–65	18–45
99 (mixed)	16 (male)	72 (mixed)	17 (mixed)	39 (mixed)	432 (mixed)	90 (mixed)
Mixed	Mixed	Mixed	Normal	Mixed	Over- weight	Normal
2013	2015	2016	2016	2015	2016	2017
United States	Germany	United States	Canada	Sweden	United Kingdom	United States
Unknown	Completed	Recruiting	Completed	Completed	Suspended (in response to COVID-19)	Active, not recruiting

COMPARATOR

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS

WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STATUS

STUDY

ANNEX 4. Characteristics of ongoing/registered trials

NCT02252952

(359)

NCT02487537
(ILIA S-2) (360)

NCT02548767

(361)

NCT02569762

(362)

NCT02580110

(363)

NCT02591134
(SWITCH) (364)

NCT03032640
(ISTAR-micro)
(365)

Provision of 2 × 355 mL/day beverages with sugars (any beverage from a range of caffeine-free, sugar- sweetened drinks), beverages with artificial sweetener (any beverage from a range of caffeine-free drinks sweetened with non-caloric sweetener) or water. Combined with a structured weight maintenance diet.

Provision of 1 L/day custom-made sweetened soft drink (contains an amount of sweetener that is isosweet compared with 100 g of sucrose in 1 L of beverage) or unsweetened soft drink.

Provision of 1) 0%, or 2) 25% of energy requirement as high-fructose corn syrup–sweetened beverages with an energy-balanced diet; or 3) 0%, or 4) 25% of energy requirement as high-fructose corn syrup–sweetened beverages with an ad libitum diet for 8 weeks. All diets, formulated to achieve a comparable macronutrient intake (55% energy as carbohydrate, 35% fat, 15% protein) among all 4 experimental arms, will be provided to the subjects throughout the entire study.

Provision of a mixed flavoured beverage sweetened with aspartame or sucralose.

Provision of a beverage (1000 mL/day) with 1) 66 g sucrose, 2) 0.220 g stevia glycosides, or 3) 0.216 g saccharin.

Participants will be provided with a list of permitted beverages (carbonated and still drinks) and are expected to consume at least 2 portions (2 × 330 mL/ day), or will be instructed to consumed water.

Provision of capsules with 1) sodium saccharin (2 × 200 mg/day), 2) placebo (2 × 500 mg/day), 3) sodium saccharin and lactisole (2 × 200 mg/day and 2 × 335 mg/day), or 4) lactisole (2 × 335 mg/day).

83 Annex 4. Characteristics of ongoing/registered trials

DESCRIPTION

DURATION

CHILDREN

10 weeks

4 weeks

2 weeks

2 months

1 month

2 weeks

Sugar

Placebo

Sugar, water

Glucose

Saccharose

Placebo (corn starch)

Water

Sucrose

Soft drink

Capsule

Soft drink

Table- top

Drink

Capsule

Drink

Aspartame + acesulfame K/stevia

Sucralose

Unspecified

Aspartame, sucralose, saccharin, stevia

Sucralose, stevia

Sucralose

Aspartame + acesulfame K, saccharin, sucralose

Sucralose

18–55

18–60

18–75

18–70

35–55

20–45

19–45

13–17

66 (mixed)

150 (female)

81 (mixed)

200 (mixed)

138 (mixed)

24 (mixed)

42 (female)

15 (mixed)

Over- weight

Mixed

Over- weight

Normal

Mixed

2017

2018

2017

2019

2017

2014

Canada

United States

Canada

Israel

Spain

Mexico

Turkey

United
States

Recruiting

Active, not recruiting

Recruiting

Completed

Recruiting

Completed

Terminated
(prematurely
unblinded
based on

outcome in
other trial;
adverse event
was reported)

COMPARATOR

MODE OF DELIVERY

NSS

AGE (YEARS)

NUMBER OF PARTICIPANTS

WEIGHT STATUS

STUDY START (YEAR)

COUNTRY

STATUS

STUDY

NCT03259685

(366)

NCT03407079
(SweetMeds
Study) (367)

NCT03543644
(STOP Sugars
NOW trial) (368)

NCT03708939

(369)

NCT04016337
(BEBESANO)
(370)

NCT04182464

(371)

NCT04904133

(372)

NCT02499705

(373)

NSS: non-sugar sweeteners.
Note: In addition, two ongoing nonrandomized controlled trials were identified: Huber T et al. (374) and Steffen et al. (375).

Provision of soft drinks (710 mL/day): 1) regular soft drinks (with sugar), 2) diet soft drinks (with aspartame and acesulfame K), 3) stevia-sweetened soft drinks (with steviol glycosides).

Provision of capsules with 1) sucralose (approximately 4 mg/kg/day) or 2) placebo. Primary aim was to investigate the effect of sucralose on drug metabolism of digoxin and midazolam.

Participants will 1) keep their regular intake of sugar- sweetened beverages, 2) replace with non-nutritive sweetened beverage, or 3) replace with water.

Consumption of glucose, sucralose, aspartame, stevia or saccharin (4 mg/day of artificial sweetener).

Provision of drink (330 mL/day) made with lemon and maqui, and sweetened with saccharose, sucralose or stevia.

Provision of capsules with 1) sucralose (3 × 90 mg/day), or 2) placebo – corn starch (3 × 90 mg/day). Instruction to consume the capsule with each meal (3/day).

Provision of water (330 mL/day) sweetened with 1) saccharin (140 mg), 2) sucralose (66 mg), 3) aspartame + acesulfame K (88 mg), or 4) nothing (control).

Provision of equisweet flavoured beverages with sucralose (2 packets), sucrose, or Splenda and maltodextrin.

84 Health effects of the use of non-sugar sweeteners

Age.......
Sex.......
Alcohol
Smoking
BMI....
Other fat
Disease risk
Total energy Sugars/SSBs Other diet

Age....... Sex....... Alcohol Smoking BMI.... Other fat Disease risk Total energy Sugars/SSBs Other diet

Anderson 2020
Angeles Perez-Ara 2020
Bao 2008
Bassett 2019

Bernstein 2012
Bes-Rastrollo 2006
Chazelas 2019
Chazelas 2020

Chia 2016
Chia 2018
Cohen 2012
de Koning 2012

Drouin-Chartier 2019
Duffey 2012
Fagherazzi 2013
Fagherazzi 2017

Farvid 2021
Ferreira-Pego 2016
Fowler 2008
Fowler 2015

Fung 2009
Gardener 2012
Gardener 2018
Garduno-Alanis 2020

Guo 2014
Haslam 2020
Hirahatake 2019
Hodge 2018

Huang 2017
Hur 2021
InterAct Consortium 2013

Jensen 2020
Keller 2020
Lana 2015
Lim 2006
Lin 2011
Ma 2016
Malik 2019 McCullough 2014 Mossavar-Rahmani 2019 Mullee 2019 Munoz-Garcia 2019 Nettleton 2009 O'Connor 2015 Paganini-Hill 2007 Palmer 2008
Parker 1997
Pase 2017
Rebholz 2017 Romanos-Nanclares 2021 Sakurai 2014 Schernhammer 2005 Schernhammer 2012 Schulze 2004
Smith 2015 Stellman 1986 Stepien 2016

Stern 2017
Tucker 2015
Vyas 2015
Wang 2019

Zhang 2021

ANNEX 5. Adjustments for potential confounders in cohort studies Table A5.1 Key adjustments in prospective cohort studies in adults

BMI: body mass index; Other fat: measures of adiposity other than BMI; Other diet: components of diet other than energy or sugars; SSBs: sugar-sweetened beverage Note: Some studies included single sex cohorts, and therefore adjusting for sex was not possible.

85 Annex 5. Adjustments for potential confounders in cohort studies

ALL COVARIATES ADJUSTED FOR IN MOST ADJUSTED MODEL	ADULTS
STUDY

Table A5.2 Complete list of adjustments in all prospective cohort studies

Anderson 2020

Angeles Pérez-Ara 2020
Bao 2008
Bassett 2020

Bernstein 2012
Bes-Rastrollo 2006

Chazelas 2019

Chazelas 2020

Chia 2016
Chia 2018

Cohen 2012
de Koning 2012

Drouin-Chartier 2019

Sociodemographic factors (age, sex, ethnic group); economic and lifestyle factors (income, qualifications, total physical activity, sedentary behaviour, smoking status, alcohol); BMI and total energy intake; potential dietary confounders (red meat, processed meat, fruit, vegetables, total fat, total fibre, total sugars intake (total sugars was not used when total sugars intake was the exposure of interest).

Study site; gender; sex; marital status; educational level; BMI; MoodFood diet score; smoking; alcohol use; physical activity; high blood pressure; diabetes; stomach or intestinal ulcer.

Sex; race; education; BMI; alcohol; smoking; physical activity; energy-adjusted red meat consumption; energy-adjusted folate consumption; total energy intake; SSB intake.

Alcohol intake; country of birth; Mediterranean diet score; physical activity (frequency and intensity); socioeconomic position; sex; smoking status; sugar-sweetened soft drink consumption.

Intakes of red meat, poultry, fish, nuts, whole- and low-fat dairy products, and fruit and vegetables; cereal fibre; alcohol intake; trans fat intake; cigarette smoking; parental history of early myocardial infarction (before age 60 years); multivitamin use; aspirin use at least once per week; vitamin E supplement use; menopausal status in women; physical exercise; sugar-sweetened sodas.

Age; sex; total energy intake from non-sugar-sweetened soft drink sources; fibre intake; alcohol intake; milk consumption; leisure-time physical activity; smoking status; snacking; television watching; baseline weight.

Age; sex; energy intake without alcohol; sugars intake from other dietary sources (all sources except sugary drinks); alcohol, sodium, lipid, and fruit and vegetable intakes; BMI; height; physical activity; smoking status; number of 24-hour dietary records; family history of cancer; educational level; the following prevalent conditions at baseline: type 2 diabetes, hypertension, major cardiovascular event (myocardial infarction or stroke), and dyslipidaemia (triglycerides or cholesterol, or both). For breast cancer: in addition to above, adjusted for the number of biological children, menopausal status at baseline, hormonal treatment for menopause at baseline and during follow-up, and oral contraception use at baseline and during follow-up.

Age; sex; BMI; sugars intake from other dietary sources; number of 24-hour dietary records; smoking status; educational level; physical activity; family history of cardiovascular disease; intakes of alcohol, energy, fruit and vegetables, red and processed meat, nuts, whole grains, legumes, saturated fatty acids, and sodium; proportion of ultraprocessed food in the diet (NOVA classification); presence of type 2 diabetes, dyslipidaemia, hypertension, hypertriglyceridemia, and treatments for these conditions (ASB and sugary drink models were mutually adjusted).

Year of visit; age; sex; age by sex interaction; race; current smoking status; dietary intake (caffeine, fructose, protein, carbohydrate, fat); physical activity; diabetes status; DASH score.

Age; sex; race and lifestyle factors including physical activity (frequency and duration); smoking status; BMI; year of recruitment; year of study visit; number of years from dietary assessment to oral glucose tolerance test assessment.

Age; race; family history of hypertension; physical activity; calcium, magnesium and vitamin D intake; cereal fibre and trans fat intake; carbohydrate consumption; DASH-style diet; total fructose consumption; daily calories; alcohol; whether or not they were trying to lose weight; smoking status; oral contraceptive use (in female cohorts); non- narcotic analgesic use; BMI, BMI2 and weight change between surveys; SSB intake.

Age; smoking; physical activity; alcohol intake; multivitamin use; family history of coronary heart disease; pre-enrolment weight change; low-calorie diet; diet quality (Alternative Healthy Eating Index); total energy intake; BMI; previous type 2 diabetes; high triglycerides; high cholesterol; high blood pressure.

Age; race; family history of diabetes; physical examination during the 4-year cycle; menopausal status and postmenopausal hormone use; oral contraceptive use; smoking status; initial and change in physical activity level; initial and change in alcohol consumption; initial BMI; initial calorie intake; initial and change in Alternative Healthy Eating Index score (calculated without the alcohol and sugary beverage components); initial and change in intakes of water, coffee, tea and milk; initial intakes of sugary beverages, or SSBs and fruit juices, and ASBs; changes in intake of ASBs, fruit juices, SSBs or sugary beverages.

86 Health effects of the use of non-sugar sweeteners

ALL COVARIATES ADJUSTED FOR IN MOST ADJUSTED MODEL

STUDY

Duffey 2012 Fagherazzi 2013 Fagherazzi 2017

Farvid 2021

Ferreira-Pego 2016

Fowler 2008
Fowler 2015

Fung 2009

Gardener 2012

Gardener 2018
Garduno-Alanis 2020
Guo 2014
Haslam 2020

Hirahatake 2019
Hodge 2018

Huang 2017

Race; sex; study centre; baseline age; BMI; smoking status; family structure; total energy intake; physical activity; maximum education reported during the study; either diet beverage consumption (in dietary pattern model) or dietary pattern (in diet beverage consumption model).

Years of education; smoking status; physical activity; hypertension; hypercholesterolaemia; use of hormone replacement therapy; family history of diabetes; self-reported use of antidiabetic drugs; alcohol intake; omega-3 fatty acid intake; carbohydrate intake; coffee intake; fruit and vegetables, and processed meat consumption; dietary pattern (Western or Mediterranean); total energy intake (excluding energy from alcohol and carbohydrates); BMI.

Alcohol consumption; carbohydrate intake; energy intake from protein and lipids; level of education; smoking status; hypertension; hypercholesterolaemia; family history of diabetes; physical activity; BMI.

Age at diagnosis; calendar year of diagnosis; time between diagnosis and first food frequency questionnaire; calendar year at start of follow-up of each 2-year questionnaire cycle; prediagnostic BMI; BMI change after diagnosis; postdiagnostic smoking; postdiagnostic physical activity; oral contraceptive use; postdiagnostic alcohol consumption; postdiagnostic total energy intake; prediagnostic menopausal status, age at menopause and postmenopausal hormone use status; postdiagnostic aspirin use; race; stage of disease; estrogen receptor/progesterone receptor (ER/PR) status; radiotherapy; chemotherapy; hormonal treatment.

Intervention group; age; sex; leisure time physical activity; BMI; smoking status; cumulative average consumption of dietary variables (vegetables, legumes, fruit, cereals, meat, fish, bakery, dairy products, olive oil, nuts); cumulative total energy intake; alcohol and alcohol squared; MetS components at baseline.

Gender; ethnicity; baseline age, education, socioeconomic index, BMI, exercise frequency and smoking status; interim change in exercise level; smoking cessation. Sex; age; ethnicity; education; neighbourhood; beginning BMI; leisure physical activity level; diabetes; smoking status; length of interval.

Age; smoking; alcohol intake; family history of disease; physical activity; aspirin use; menopausal status and postmenopausal hormone use; history of hypertension and high blood cholesterol; diet quality (Alternative Healthy Eating Index).

Demographics (age, sex, race/ethnicity, education); behavioural risk factors (smoking, moderate alcohol use, moderate to heavy physical activity); daily diet (total calories, grams of protein, grams of total fat, grams of saturated fat, grams of carbohydrates, mg of sodium); BMI; daily diet; vascular risk factors (previous cardiac disease, peripheral vascular disease, history of diabetes, history of hypercholesterolaemia, history of hypertension, metabolic syndrome); waist circumference; blood sugar; HDL cholesterol, LDL cholesterol and triglycerides; mutually adjusted for each type of soft drink.

Age; sex; race/ethnicity; Mediterranean diet; total calories; smoking; physical activity; moderate alcohol use; BMI; hypertension; hypercholesterolaemia.

Age; sex; education; marital status; smoking, alcohol consumption; physical activity; energy consumption; fruit and vegetable consumption; cardiovascular disease, cancer or diabetes in medical history.

Age at baseline; sex; race; education level; marital status; smoking status; consumption of beer, liquor and wine; physical activity (frequency); BMI; energy intake.

Age; sex; total energy; education; current smoking status; current diabetes mellitus status; physical activity index; alcohol; waist circumference; servings/day of vegetables, whole fruits, whole grains, nuts/seeds and seafood; percentage energy from saturated fat; mutual adjustment for SSBs, low-calorie sweetened beverages and fruit juices.

Study centre; education; smoking; dieting behaviour; cumulative average energy intake; cumulative average physical activity; cumulative average Mediterranean diet score; baseline BMI; weight changes from baseline to diabetes diagnosis; censoring or end of follow-up (whichever came first) as a potential mediator; SSB intake.

SEIFA (Socio-Economic Indexes for Area); country of birth; alcohol intake; smoking status; physical activity; Mediterranean diet score; sugar-sweetened soft drink consumption; waist circumference.

Age; race; marital status; family income; education; family history of diabetes; BMI; change in BMI; waist-to-hip ratio; systolic blood pressure; health insurance status; antihypertensive use; antihyperlipidemic use; hormone replacement therapy use; calibrated energy intake; SSB consumption; glycaemic load based on available carbohydrates; glycaemic index based on available carbohydrates; Alternative Healthy Eating Index; cardiovascular history; hysterectomy history; smoking status; physical activity; sitting time; alcohol consumption.

87 Annex 5. Adjustments for potential confounders in cohort studies

ALL COVARIATES ADJUSTED FOR IN MOST ADJUSTED MODEL

STUDY

Hur 2021

InterAct Consortium 2013 Jensen 2020

Keller 2020

Lana 2015

Lim 2006
Lin 2011

Ma 2016

Malik 2019

McCullough 2014
Mossavar-Rahmani 2019

Mullee 2019

Muñoz-Garcia 2019

Nettleton 2009
O’Connor 2015
Paganini-Hill 2007
Palmer 2008

Age; energy intake; race; height; BMI; menopausal status and menopausal hormone; family history of colorectal cancer; pack years of smoking; physical activity; regular use of aspirin; regular use of nonsteroidal anti-inflammatory drugs; current use of multivitamins; intake of alcohol, red and processed meat, dietary fibre, total folate (from foods and supplements) and total calcium; Alternative Healthy Eating Index 2010 score without SSBs and alcohol; lower endoscopy due to screening or for other indications within the past 10 years.

Sex; educational level; physical activity; smoking status; alcohol consumption; consumption of sugar-sweetened soft drinks; consumption of juice.

Age; sex; study site; BMI; education; steps per day; smoking; self-reported quality of life; total calories consumed per day; percentage of total calories from saturated fat; fruit and vegetable servings per day; processed meat servings per day; total fibre consumed per day; SSB consumption.

SSB intake; smoking; physical activity; education; alcohol; diet (cereal fibres, trans fat, polyunsaturated fat/saturated fat ratio); total energy; BMI; baseline hypertension; high cholesterol.

Age; sex; educational level; current smoker; sleep; living alone; energy intake; coffee consumption; Mediterranean diet score; alcohol consumption; current dieting; weight loss of 45 kg in the past 4 years; leisure physical activity; BMI; hypertension; diabetes; hypercholesterolaemia; self-reported disease (cardiovascular disease, cancer, asthma or chronic bronchitis, sleep apnoea, peptic ulcer, cholelithiasis, cirrhosis, osteoarthritis, hip fracture, eye cataract, periodontal disease).

Age at study entry; sex; ethnicity; BMI; history of diabetes. Age; caloric intake; hypertension; BMI; diabetes; cigarette smoking; physical activity; cardiovascular disease.

Baseline outcome values; sex; age; smoking status; physical activity score; energy intake; alcohol intake; saturated fat intake; SSB intake; multivitamin use; intake of whole grains, fruits, vegetables, coffee, nuts and fish; change in body weight.

Age; smoking; alcohol intake; postmenopausal hormone use (for Nurses’ Health Study cohort); physical activity; family history of diabetes; family history of myocardial infarction; family history of cancer; multivitamin use; ethnicity; aspirin use; baseline history of hypertension and hypercholesterolaemia; intake of whole grains, fruit, vegetables, and red and processed meat; total energy; BMI; SSB intake.

Age at baseline; gender; history of diabetes; BMI; smoking status; energy intake; SSB intake.

Age; race; education; diabetes mellitus; cardiovascular diseases; high cholesterol requiring medication; hypertension (defined as blood pressure ≥140/90 mmHg); BMI; smoking; alcohol; Healthy Eating Index; MET.

BMI; physical activity index; educational status; alcohol consumption; smoking status and intensity; smoking duration; ever use of contraceptive pill; menopausal status; ever use of menopausal hormone therapy; intakes of total energy, red and processed meat, fruits and vegetables, coffee, and fruit and vegetable juice; stratified by age, EPIC center and sex.

Sex; age at baseline; STICS-m (Spanish version of the modified Telephone Interview of Cognitive Status); Apolipoprotein E ε4; years of university education; follow-up time until baseline STICS-m score; hypertension; HDL and total cholesterol; BMI; smoking; cardiovascular diseases; prevalent diabetes; physical activity; Mediterranean diet adherence score; total energy intake.

Study site; age; sex; race/ethnicity; energy intake; education; physical activity; smoking status; pack-years; weekly or more supplement use; waist circumference; BMI.

Age; sex; social class; education level; family history of diabetes; physical activity level; smoking status; alcohol consumption; season; intake of other sweet beverages; total energy intake; BMI; waist circumference.

Age; sex; smoking; exercise; BMI; alcohol intake; history of hypertension, angina, heart attack, stroke, diabetes, rheumatoid arthritis and cancer.

Age; questionnaire cycle; education; physical activity; smoking status; family history of diabetes; intake of red meat, processed meat, cereal fibre and coffee; glycaemic index; intake of SSBs and juice.

Age; smoking status; BMI; aerobic activity; total energy intake.

Parker 1997

88 Health effects of the use of non-sugar sweeteners

ALL COVARIATES ADJUSTED FOR IN MOST ADJUSTED MODEL

STUDY

Pase 2017 Rebholz 2017

Romanos-Nanclares 2021

Sakurai 2014
Schernhammer 2005
Schernhammer 2012

Schulze 2004

Smith 2015
Stellman 1986
Stepien 2016

Stern 2017

Tucker 2015
Vyas 2015

Wang 2019

Zhang 2021

Age; sex; total caloric intake; systolic blood pressure; treatment of hypertension; prevalent cardiovascular disease; atrial fibrillation; left ventricular hypertrophy; total cholesterol; HDL cholesterol; prevalent diabetes mellitus; waist-to-hip ratio.

Age; sex; race; education level; smoking status; physical activity; total caloric intake; baseline estimated glomerular filtration rate; BMI; diabetes; systolic blood pressure; serum uric acid; diet quality (modified Alternative Healthy Eating Index 2010); dietary sodium; dietary fructose; frequency of consumption of sugar-sweetened beverages.

Age; SSB or NSS-sweetened beverage intake; race; age at menarche; age at menopause; postmenopausal hormone use; history of oral contraceptive use; parity and age at first birth; breastfeeding history; family history of breast cancer; history of benign breast disease; height; cumulatively updated alcohol intake; cumulatively updated total caloric intake; physical activity; BMI at age 18 years; modified Alternative Healthy Eating Index score (with SSBs and alcohol removed); socioeconomic status; change in weight since age 18 years.

Age; BMI; family history of diabetes; smoking; alcohol drinking; habitual exercise; presence of hypertension; presence of dyslipidaemia; receiving diet treatment for chronic disease; total energy intake; total fibre intake; consumption of SSB; fruit juice consumption; vegetable juice consumption; coffee consumption.

Age; gender; follow-up cycle; history of diabetes; smoking status; caloric intake; nonvigorous physical activity; SSB intake.

Age; questionnaire cycle; sugar-sweetened soda consumption; fruit and vegetable consumption; multivitamin use; intakes of alcohol, saturated fat, animal protein and total energy; race; BMI; height; discretionary physical activity; smoking history; menopausal status and use of hormone replacement therapy (women only).

Age; alcohol intake; physical activity; smoking, postmenopausal hormone use; oral contraceptive use; cereal fibre intake; total fat intake; BMI; baseline energy intake from non-soda sources and changes over time; baseline intake of red meat, French fries, processed meat, sweets, snacks, vegetables and fruits; and changes in confounders over time.

Age; BMI at the beginning of each 4-year period; sleep duration; prevalent levels of and changes in (specific to the analysis) physical activity, alcohol use, amount of time spent watching television, smoking, and all dietary components simultaneously.

Not adjusted per se, but rather participants selected to have equivalent sex; age; socioeconomic status; cigarette smoking; and no history of diabetes, heart disease or cancer – conditions that may affect both weight and dietary behaviour (including artificial sweetener use).

Non-alcoholic energy intake; BMI; sex-specific physical activity; education level; alcohol intake at recruitment and alcohol intake pattern; smoking intensity, duration and history; diabetes status; stratified by age, sex and study centre

Baseline sugar-sweetened soda consumption; age; state; 2006 and 2008 physical activity; baseline smoking status; alcohol consumption; oral contraceptive use; menopausal status; postmenopausal hormone therapy use; changes in smoking status, alcohol consumption and consumption of red meat, dairy, yoghurt, fruit, vegetables, nuts, white bread, flour tortillas, corn tortillas, orange or grapefruit juice, and homemade sweetened beverages.

Age; menopausal status; baseline body weight; physical activity.

Age; race; education and income; smoking status; BMI; history of diabetes, hypertension or hyperlipidaemia; alcohol intake; log calibrated energy intake; physical activity; SSB intake; salt intake; hormone therapy.

Age at the carotid scan; race/ethnicity; education level; financial strain; self-rated overall health; BMI; smoking status; nonoccupational physical activity level; menopausal status; use of hormone therapy from baseline to the visit of the carotid scan; number of missing visits for dietary measurements; total energy intake; Alternative Healthy Eating Index; intake of tea; intake of alcoholic beverages; intake of beverage condiments; elevated blood pressure; elevated fasting glucose; elevated triglycerides; reduced HDL cholesterol.

Age; sex; family income-poverty ratio level; race; education level; marital status; alcohol consumption; smoking; leisure-time physical activity; BMI; prevalent high cholesterol level; hypertension; diabetes; history of cardiovascular disease and cancer; 2015 healthy eating index score; total energy intake; simultaneously included intakes of SSBs and ASBs.

89 Annex 5. Adjustments for potential confounders in cohort studies

ALL COVARIATES ADJUSTED FOR IN MOST ADJUSTED MODEL	CHILDREN
STUDY

PREGNANT WOMEN

Berkey 2004 (GUTS)
Blum 2005
Davis 2018 (SOLAR)
Field 2014 (GUTS II) Haines 2012 (EAT)
Kral 2008

Laska 2012 (IDEA, ECHO)
Ludwig 2001

Macintyre 2018 (GUS)
Marshall 2003 (IFS)
Newby 2004 (North Dakota

WIC Program for Children)
Striegel-Moore 2006 (NGHS)

Vanselow 2009 (EAT)
Zheng 2015a (CAPS)

Zheng 2015b (Healthy Start
Study)

Zheng 2019 (Raine)

Azad 2016 (CHILD)
Chen 2009 (NHS II)
Cohen 2018 (Project Viva)

Dale 2019 (MoBa)
Englund-Ogge 2012 (MoBa)
Gillman 2017 (Project Viva)
Gunther 2019 (GeliS)

Sex; age; Tanner stage of development; race; menarche (girls) ; prior BMI z-score; height growth; milk type; physical activity; inactivity; intake of SSB and other beverages. Unclear. Sex; Tanner stage of development at baseline and 1-year follow-up; energy intake; BMI z-score. Age; time between assessments; BMI at start of the period; Tanner stage of development; hours per day of television viewing; hours per week of vigorous activity. Age cohort; socioeconomic status; race/ethnicity. Change in BMI z-score or waist circumference at ages 3–5 years; total energy intake from food at age 3 years. Physical activity; stage of puberty; race; parental education; eligibility for free/reduced-price lunch; age; study; total energy intake.

Baseline anthropometrics (BMI and triceps-skinfold thickness); demographics (age, sex, ethnicity); indicator variables for schools (the largest as the omitted category); diet (percentage energy from fat at baseline, energy-adjusted fruit juice intake at baseline, change in these variables from baseline to follow-up); physical activity; time spent watching television and videos; change in time spent watching television and videos; total energy intake.

Unclear.
Age at dental examination; sex; fluoride exposure; dietary variables significant at P < 0.10 in univariate analysis.

Age; sex; energy; sociodemographic variables; ethnicity; residence; level of poverty; maternal education; birthweight.

Consumption of other types of beverages; site; visit; race; total caloric intake (in all models except that with caloric intake as the dependent variable).

Age; sex; race/ethnicity; socioeconomic status; baseline BMI; baseline of same beverage; all baseline beverages; baseline and time strenuous physical activity; time weekday television watching; coffee and tea consumption.

Age; gender; BMI z-score at age 8 years; Socioeconomic Index for Area scores; maternal age at birth; parental education level; parental countries of birth; maternal age at birth; presence of gestational diabetes; breastfeeding characteristics; pubertal status; study randomization group; total energy intake.

Age; BMI z-score; sex; intervention allocation; physical activity; whether parents were divorced; number of siblings living with the child; annual income; maternal education level; paternal education level; maternal pre-pregnancy overweight; beverage intake residuals with adjustment for total energy intake; energy intake from non-beverage sources.

Baseline BMI; waist circumference; overweight or obesity; intakes of water, tea/coffee, diet drink, 100% fruit juice and milk; age; gender; dietary misreporting; physical activity; maternal education; family income; healthy dietary pattern; western dietary pattern scores at age 4 years; total energy intake.

Maternal total energy intake; Healthy Eating Index score; maternal postsecondary education; maternal smoking and diabetes during pregnancy; breastfeeding duration; infant sex; introduction of solid foods before 4 months; SSB intake.

Age; parity; race/ethnicity; cigarette smoking status; family history of diabetes in a first-degree relative; alcohol intake; physical activity; BMI; western dietary pattern score.

Maternal age; pre-pregnancy BMI; parity; college graduate; fish intake (average of first and second trimesters); smoking during pregnancy; household income at enrolment; corresponding intake during pregnancy (i.e. sucrose, fructose, SSBs, fruit juice, diet soda); child sex, race/ethnicity, and birthweight for gestational age z-score.

Year of birth; smoking before pregnancy; mother’s age; education; parity; diabetes mellitus; pre-pregnancy BMI. Preterm delivery; maternal age; pre-pregnancy BMI; height; total energy intake; marital status; parity; smoking during pregnancy; education; SSB intake. Maternal age; race/ethnicity; education; smoking; parity; prepregnancy BMI; household income; child age and sex; child beverage intake. Pre-pregnancy BMI; age; parity; group assignment.

90 Health effects of the use of non-sugar sweeteners

ALL COVARIATES ADJUSTED FOR IN MOST ADJUSTED MODEL

STUDY

Halldorsson 2010 (Danish National Birth Cohort)

Hinkle 2019 (DWH)

Hrolfsdottir 2019 (PREWICE)

Maternal age; height; pre-pregnancy BMI; total energy intake; cohabitant status; parity; smoking during pregnancy; familial socio-occupational status.

Current age; pre-pregnancy BMI at the index pregnancy; primiparous; smoking; moderate or vigorous physical activity; pre-pregnancy chronic diseases; Alternative Healthy Eating Index; coffee intake; tea intake.

Maternal pre-pregnancy BMI; age; parity; smoking during pregnancy; educational level; total gestational length; offspring sex.

Maslova 2013 (Danish National
Maternal age; smoking; parity; prepregnancy BMI; physical activity; breastfeeding; socioeconomic position; child sex; maternal history of asthma; maternal history of Birth Cohort)
allergies; paternal history of asthma; paternal history of allergies; energy intake. Munda 2019
Paternal height; employment status; glycated haemoglobin (HbA1c). Petherick 2014 (BiB)
Maternal age; booking BMI; height; marital status; parity; smoking; education; ethnicity; SSB intake. Renault 2015 (TOP study)
Energy intake; maternal age; smoking during pregnancy; parity; pre-pregnancy BMI; intervention group. Salavati 2020
Energy intake; maternal BMI; maternal age; smoking; alcohol; education level; urbanization level; parity; sex of newborn; ethnicity; intake of other 21 food groups. Schmidt 2020
Maternal age; region of residence; maternal energy intake; calendar year of pregnancy onset; birth order; maternal pre-pregnancy diabetes; BMI; smoking; alcohol consumption; physical activity; socioeconomic position; gestational diabetes in previous pregnancy.

Zhu 2017 (DWH)

Maternal: pre-pregnancy BMI; age; socioeconomic status; smoking during pregnancy; intakes of total energy, desserts and sweets, oil/margarine/butter, potato, processed meat, refined grains, whole grains and SSBs during pregnancy; physical activity during pregnancy. Offspring: sex, breastfeeding duration, consumption of artificially and sugar-sweetened beverages at 7 years (only for outcomes at 7 years), physical activity at 7 years (only for outcomes at 7 years).

ASB: artificially-sweetened beverage; BMI: body mass index; DASH: Dietary Approaches to Stop Hypertension; HDL: high-density lipoprotein; LDL: low-density lipoprotein; MET: metabolic equivalent of task (the caloric need per kilogram of body weight per hour of activity divided by the caloric need per kilogram per hour at rest); MetS: metabolic syndrome; SSB: sugar-sweetened beverage.

91 Annex 5. Adjustments for potential confounders in cohort studies

ANNEX 6.

Risk of bias assessment

Figure A6.1. Risk of bias in randomized controlled trials (Cochrane risk of bias tool)

92 Health effects of the use of non-sugar sweeteners

TOTAL (MAX 9)

ADEQUACY OF FOLLOW-UP OF COHORTS

ADEQUACY OF LENGTH OF FOLLOW-UP

ASSESSMENT OF OUTCOME

COMPARABILITY OF COHORTS

OUTCOME OF INTEREST NOT PRESENT AT START OF STUDY

ASCERTAINMENT OF EXPOSURE

SELECTION OF NON-EXPOSED COHORT

REPRESENTATIVENESS OF EXPOSED COHORT

STUDY

Table A6.1 Risk of bias in prospective cohort studies (Newcastle–Ottawa scale)

Acero 2020 (Talking Health) Anderson 2020 (UK Biobank) Angeles Pérez-Ara 2020 (MooDFOOD) Azad 2016 (CHILD)

Bao 2008 (NIH-AARP Diet and Health Study) Bassett 2020 (MCCS)
Berkey 2004 (GUTS)
Bernstein 2012 (NHS, HPFS)

Bes-Rastrollo 2006 (SUN)
Blum 2005
Chazelas 2019 (NutriNet-Santé)
Chazelas 2020 (NutriNet-Santé)

Chen 2009 (NHS II)
Chia 2016 (BLSA)
Chia 2018 (BLSA)
Cohen 2018 (Project Viva)

Cohen 2012 (NHS, NHS II, HPFS)
Dale 2019 (MoBa)
Davis 2018 (SOLAR)
de Koning 2012 (HPFS)

Drouin-Chartier 2019 (NHS, NHS II, HPFS)
Duffey 2012 (CARDIA)
Englund-Ogge 2012 (MoBa)
Fagherazzi 2013 & 2017 (E3N)

Farvid 2021 (NHS and NHS II)
Ferreira-Pego 2016 (PREDIMED)
Field 2014 (GUTS II)
Fowler 2008 (SALSA)

Fowler 2015 (SALSA)
Fung 2009 (NHS)

– ì ì
ì ì ì
– ì ì
ì ì ì
ì ì –
ì ì ì
ì ì ì
– ì ì
ì ì ì
– ì ì
– ì ì
ì ì ì
– ì ì
– ì ì
– ì ì
– ì ì
– ì ì
ì ì ì
– ì ì
– ì ì
– ì ì
ì ì ì
ì ì ì
– ì ì
– ì ì
– ì ì
– ì ì
– ì ì
– ì ì
– ì ì

––ì ì – 4 ì ìì ì ì – 8 ì – – ì – 4 – ìì ì ì 7 ì ìì ì ì – 7 ì ìì ì – 7

– ì ì 7 ì ì ì 8 – ì – 4 – –ì ì – 4

ì ìì ì ì ì 8 ì ìì ì ì – 8 ì ìì – ì ì 7 ì ìì ì ì ì 8 – – ì ì – 4 – ì ì ì ì 6 ì ìì – ì – 6 ì ìì ì – 7

ì ì ì ìì – –

– –

ì ì ì ìì ì ì ì ì ì ì ì ì ì ì – ì – ìì

ì ì – 4 – ì ì 6 – ì ì 7 ì ì – 7 ì ì – 7 ì ì ì 7 – ì – 5 ì ì – 6 – ì – 4 ì ì – 6

– ìì ì – 5 ì ì– ì ì 6

93 Annex 6. Risk of bias assessment

TOTAL (MAX 9)

ADEQUACY OF FOLLOW-UP OF COHORTS

ADEQUACY OF LENGTH OF FOLLOW-UP

ASSESSMENT OF OUTCOME

COMPARABILITY OF COHORTS

OUTCOME OF INTEREST NOT PRESENT AT START OF STUDY

ASCERTAINMENT OF EXPOSURE

SELECTION OF NON-EXPOSED COHORT

REPRESENTATIVENESS OF EXPOSED COHORT

STUDY

ì

–

ì

Gardener 2012 (NOMAS) Gardener 2018 (NOMAS) Garduno-Alanis 2020 (HAPIEE) Gearon 2014 (MCCS)
Gillman 2017 (Project Viva) Gunther 2019 (GeliS)

Guo 2014 (NIH-AARP Diet and Health Study) Haines 2012 (EAT)

Halldorsson 2010 (Danish National Birth Cohort)

Haslam 2020 (FOS)
Hinkle 2019 (DWH)
Hirahatake 2019 (CARDIA)
Hodge 2018 (MCCS)

Hrolfsdottir 2019 (PREWICE)
Huang 2017 (WHI-OS)
Hur 2021 (NHS II)
InterActConsortium 2013 (EPIC-InterAct)

Jensen 2020 (Strong Heart Family Study)
Keller 2020 (HPP)
Kral 2008
Lana 2015 (ENRICA)

Laska 2012 (IDEA and ECHO)
Lim 2006 (NIH-AARP Diet and Health Study)
Lin 2011 (NHS)
Ludwig 2001

Ma 2016 (FHS 3rd Generation)
Macintyre 2018 (GUS)
Maslova 2013 (Danish National Birth Cohort)
Malik 2019 (NHS, HPFS)

Marshall 2003 (IFS)

ì ì –ì ì ì –ì

ìì ì ì ì ì ì

ì 8 ì 7 – 7 – 4 ì 6 ì 6 – 5 ì 5

ì 8 – 5 – 8 ì 8 ì 4 – 7 ì 6 – 7 – 6 – 7 – 4 ì 5 ì 6 ì 7 ì 6 ì 6 – 6 ì 9 ì 7 ì 8

ì ì ì ì ì – – ì ì

– ì ì ì ì – – ì ì

– ì ì – ì ì ì ì ì ì ì ì – ì ì ì ì ì – ì ì – ì ì – ì ì – ì ì – ì ì

ì ì –
– ì ì
ì ì –
– ì ì
– ì ì
– ì ì
ì ì ì
ì ì ì
– ì ì
– ì ì

ì ì

– ì
– ì
– ì

ì ì – ì

ì ì – ì ì ì ì ì – ì – ì

ì ìì ì ì – ìì ì

ì ìì ì ì
ì ìì ì

– – – ì

ì ìì – ì
ì ì – ì
ì ìì ì ì
ì ìì – ì
ì ìì ì ì

– – ì ì
– ì – ì
– ì ì ì

ì ì ì ì

– ì ì ì
– ì ì ì
– ìì ì ì

ì ìì ì ì – ì ì ì ì ìì ì ì

–– ì ì –4

94 Health effects of the use of non-sugar sweeteners

TOTAL (MAX 9)

ADEQUACY OF FOLLOW-UP OF COHORTS

ADEQUACY OF LENGTH OF FOLLOW-UP

ASSESSMENT OF OUTCOME

COMPARABILITY OF COHORTS

OUTCOME OF INTEREST NOT PRESENT AT START OF STUDY

ASCERTAINMENT OF EXPOSURE

SELECTION OF NON-EXPOSED COHORT

REPRESENTATIVENESS OF EXPOSED COHORT

STUDY

–

ì

–

ì

–

ì

–

ì

–

ì

–

McCullough 2014 (CPS-II)

Mossavar-Rahmani 2019 (WHI-OS)

Mullee 2019 (EPIC)

Munda 2019

Muñoz-Garcia 2019 (SUN)

Nettleton 2009 (MESA)

Newby 2004 (North Dakota WIC Program for Children)

OConnor 2015 (EPIC-Norfolk)

Paganini-Hill 2007 (Leisure World Cohort
Study)

Palmer 2008 (BWHS)
Park 2020 (FHS, FOS)
Parker 1997 (PHHP)
Pase 2017 (FOS)

Petherick 2014 (BiB)
Rebholz 2017 (ARIC)
Renault 2015 (TOP study)
Romanos-Nanclares 2021 (NHS and NHS II)

Sakurai 2014
Salavati 2020 (Perined-Lifelines Cohort)
Schernhammer 2005 (NHS, HPFS)
Schernhammer 2012 (NHS, HPFS)
Schmidt 2020 (Danish National Birth Cohort)
Smith 2015 (NHS, NHS II, HPFS)
Stellman 1986 (American Cancer Society

study)
Stepien 2016 (EPIC)
Stern 2017 (Mexican Teachers Cohort)
Striegel-Moore 2006 (NGHS)
Tucker 2015

– ì ì ì ì ì – ì ì – ì ì – ì ì ì ì –

– ì ì

– ì ì – ì ì – ì ì – ì ì – ì ì – ì – – ì ì – ì ì – ì ì

ì ì – – ì ì – ì ì

ì ì –
– ì ì

– ì ì
– ì ì
– ì ì
– ì ì

ì ì ì – – ì

ì

ì ì – ì – ì ì ì ì ì ì ì ì ì

ìì –ì –6 ì ì ì –7 ìì ì ì ì 8 –ì ì – 4 ìì – ì ì 6 ì ì ì ì 7

ìì ì ì – 7

– – ì ì 5 ìì ì ì – 7 ì ì ì – 5 ì ì ì – 6 ìì ì ì – 6 ìì ì ì – 6 ì – ì ì 6 ì – ì – 5 ìì ì ì ì 8 ìì ì ì – 7 ìì – ì ì 7 ìì ì ì ì 8 ìì ì ì – 7 ìì – ì – 6

3 ì ìì ì ì 7 – ìì – ì – 5 –ìì ì ì 6

––ì ì – 4

95 Annex 6. Risk of bias assessment

TOTAL (MAX 9)

ADEQUACY OF FOLLOW-UP OF COHORTS

ADEQUACY OF LENGTH OF FOLLOW-UP

ASSESSMENT OF OUTCOME

COMPARABILITY OF COHORTS

OUTCOME OF INTEREST NOT PRESENT AT START OF STUDY

ASCERTAINMENT OF EXPOSURE

SELECTION OF NON-EXPOSED COHORT

REPRESENTATIVENESS OF EXPOSED COHORT

STUDY

TOTAL SCORE (MAX 9)

NONRESPONSE RATE

SAME METHOD OF ASCERTAINMENT FOR CASES AND CONTROLS

ASSESSMENT OF EXPOSURE

COMPARABILITY OF CASES AND CONTROLS

DEFINITION OF CONTROLS

SELECTION OF CONTROLS

REPRESENTATIVE- NESS OF CASES

DEFINITION OF CASES

STUDY

Vyas 2015 (WHI-OS) Vanselow 2009 (EAT)
Wang 2019 (SWAN)
Zheng 2015a (CAPS)
Zheng 2015b (Healthy Start Study) Zheng 2019 (Raine)

Zhu 2017 (DWH)
Zhang 2021 (NHANES)

ì ì – ì – ì – ì ì ì – ì ì ì

ìì ì

ì ì ì ì ì ì ì ì

ì ìì –ì –ì –ì –ìì –ì –ìì ìì

ì

–

ì ì ì ì ì ì

ì ì 9 ì ì 5 ì – 5 ì – 5 ì – 7 ì – 5 ì – 7 – – 7

Table A6.2
Risk of bias in case–control studies (Newcastle–Ottawa scale)

Akdas 1990
Andreatta 2008
Asal 1988
Bosetti 2009

Bravo 1987
Bunin 2005
Cabaniols 2011
Cartwright 1981

Chan 2009
Connolly 1978
Ewertz 1990
Gallus 2007

Gold 1985
Goodman 1986
Gurney 1997
Hardell 2001

Hoover 1980
Howe 1977 and 1980

ì – – ììì – ì– 5
ì – – ììì – ì– 5
ì – ì – – – – – 2
ì – – ììì – ìì 6
ì – – ìì – ì– 4
ì ì
ì – ìì – ì– 6

– ì
–
–ì – ì– 3 –ì– –ì–ì– 3 – – ì
– ìì – ìì 5 – – –
– ì– – – 1 – ì ì
ì ìì ì – 6 ì – –
– ìì – ì ì 5 – – ì
ì ìì – ì – 5 ì ì –
ì ì – ì ì 6 – – ì
– ìì – –– 3 ì – ì
– ìì ìì 6 ì ì ì
– ìì – ìì 7 – ì ì
– ì– ì– 4

96 Health effects of the use of non-sugar sweeteners

TOTAL SCORE (MAX 9)

NONRESPONSE RATE

SAME METHOD OF ASCERTAINMENT FOR CASES AND CONTROLS

ASSESSMENT OF EXPOSURE

COMPARABILITY OF CASES AND CONTROLS

DEFINITION OF CONTROLS

SELECTION OF CONTROLS

REPRESENTATIVE- NESS OF CASES

DEFINITION OF CASES

STUDY

Iscovich 1978
Kessler 1976 and 1978 Kobeissi 2013
Mahfouz 2014
Mettlin 1989 Moller-Jensen1983
Momas 1994

Mommsen 1983
Morgan 1974
Morrison 1979
Morrison 1980

Morrison 1982 (Japan)
Morrison 1982 (United Kingdom)
Najem 1982
Nomura 1991

Norell 1986
Ohno 1985
Radosavljevic 2001
Risch 1988

Silverman 1983
Simon 1975
Sullivan 1982
Wynder 1977

Wynder 1980
Yu 1997
Zou 1990

ì –ì –ì– – ì 4

ì ì– ì ì –– ì ì – ì ì – ì– ì ììì – ì ì ì – – – ì – ì – – – – ì – – ì ì ì – ì ì ì – ì ì ì – ì – – – ì ì ì – ì ì ì – ì ì ì – ì ì – ì – – ì – ì ì ì – – – – ì – – ì – ì – – ì ì – ì ì ì – – – ì ì – ì

ìì ì

– – ì – ìì ì ì – ìì – ìì – ì ì ì – ì – ì – ì – ì – ìì – ì ì ìì – ì – ìì – ì – ì ì – – ì ì – – ìì – ì–

ì – 7 ì – 3 ì – 5 ì – 6 ì – 5 – – 5 ì – 4 ì – 4 ì – 3 ì ì 6 ì ì 6 ì ì 6 ì – 3 ì ì 7 ì – 6 ì ì 7 ì – 5 ì – 4 ì ì 6 ì ì 5 – – 1 ì – 5 – – 3 ì – 4 ì – 5

97 Annex 6. Risk of bias assessment

CERTAINTY6

Adiposity: body weight (kg)

EFFECT

ABSOLUTE – PER 10005 (95% CI)

Adiposity: BMI (kg/m2)

Adiposity: incident obesity

Adiposity: abdominal obesity

Adiposity: waist-to-hip ratio

–

275 more

(from 91 more to 539 more)

163 more

(from 44 fewer to 474 more)

–

MD –0.71

(–1.13 to –0.28)

MD –0.12

(–0.40 to 0.15)

MD –0.01

(–0.67 to 0.64)

MD –0.14

(–0.30 to 0.02)

MD 0.14

(0.03 to 0.25)

HR 1.76

(1.25, 2.49)

HR 1.33

(0.91 to 1.96)

MD 0.00

(–0.01 to 0.01)

1181

118457

11874

917

80583

603/1668 (36.2%)

5381/10895 (49.4%)

1252

940

121

None

Not serious

Not serious10

Not serious12

Not serious

Not serious 13

Serious14

Serious16

Not serious

Serious8

Not serious

Serious8

Not serious

Serious8

Not serious

Serious7

Not serious9

Serious11

Serious7

Not serious9

Serious15

RCT

Observational
(continuous)

Observational
(high vs low)

RCT

Observational
(high vs low)

Observational

RCT

RELATIVE/MEAN DIFFERENCE4 (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER3

IMPRECISION

INDIRECTNESS2

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN1

NO. OF
STUDIES/
COHORTS

ANNEX 7. GRADE evidence profiles

GRADE evidence profile 1 Question: What is the effect of higher vs lower intake of non-sugar sweeteners in adults? Population: General adult population

29
4
5

23
5

十十◯◯

LOW

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

十十◯◯

LOW

十◯◯◯

VERY LOW

十十◯◯

LOW

十◯◯◯

VERY LOW

十十◯◯

LOW

98 Health effects of the use of non-sugar sweeteners

CERTAINTY6

Adiposity: waist circumference (cm)

EFFECT

ABSOLUTE – PER 10005 (95% CI)

Adiposity: fat mass (kg)

Adiposity: fat mass (%)

Adiposity: lean mass (kg)

Diabetes: incident diabetes

Diabetes: fasting glucose (mmol/L)

Diabetes: fasting insulin (pmol/L)

Diabetes: HbA1c (%)

Diabetes: HOMA-IR

–

16 more

(from 10 more to 22 more)

12 more

(from 8 more to 17 more)

–

MD –0.24

(–1.06 to 0.58)

MD 0.92

(–1.73 to 3.56)

MD –0.54

(–1.56 to 0.49)

MD –0.11

(–0.78 to 0.56)

MD –0.29

(–0.70 to 0.11)

HR 1.23

(1.14 to 1.32)

HR 1.34

(1.21 to 1.48)

MD –0.01

(–0.05 to 0.04)

MD –0.49

(–4.99 to 4.02)

MD 0.02

(–0.03 to 0.07)

MD 0.03

(–0.32 to 0.38)

564

12886

286

414

284

28222/408609 (6.9%)

2250/62582 (3.6%)

650

315

199

329

688

332

343

255

844

444

212

457

None

None19

None

Not serious10

Serious14

Not serious10

Not serious

Not serious10

Serious14

Serious16

Not serious10

Not serious

Serious8

Not serious

Serious8

Not serious

Serious8

Not serious17

Not serious9

Not serious18

Not serious9

Serious20

Not serious21

Not serious22

Serious23

RCT

Observational (high vs low)

RCT

Observational
(beverages)

Observational
(tabletop)

RCT

RELATIVE/MEAN DIFFERENCE4 (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER3

IMPRECISION

INDIRECTNESS2

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN1

NO. OF STUDIES/ COHORTS

10
3

十十十◯

MODERATE

十◯◯◯

VERY LOW

十十◯◯

LOW

十十◯◯

LOW

十十十十

HIGH

十十◯◯

LOW

十十◯◯

LOW

十十十◯

MODERATE

十十◯◯

LOW

十十十◯

MODERATE

十十◯◯

LOW

99 Annex 7. GRADE evidence profiles

CERTAINTY6

Diabetes: high fasting glucose

EFFECT

ABSOLUTE – PER 10005 (95% CI)

Dental caries

All-cause mortality

Cardiovascular diseases: cardiovascular disease mortality

Cardiovascular diseases: cardiovascular events

Cardiovascular diseases: coronary heart disease

Cardiovascular diseases: stroke

114 more

(from 5 more to 245 more)

In a 6-month RCT among adults (26)27, the participants who were assigned to consume sugar- sweetened or NSS-sweetened soft drinks did not develop caries or acid erosion of the enamel during the intervention.

14 more

(from 6 more to 23 more)

4 more

(from 2 more to 7 more)

12 more

(from 6 more to 19 more)

8 more

(from 1 fewer to 19 more)

2 more

(from 1 more to 4 more)

HR 1.21

(1.01 to 1.45)

HR 1.12

(1.05 to 1.19)

HR 1.19

(1.07 to 1.32)

HR 1.32

(1.17 to 1.50)

HR 1.16

(0.97 to 1.39)

HR 1.19

(1.09 to 1.29)

6086/11213 (54.3%)

102677/860873 (11.9%)

13089/598951 (2.2%)

6384/166938 (3.8%)

10104/205455 (4.9%)

8346/655953 (1.3%)

None

Not serious

Very serious26

Not serious

Serious14

Not serious

Unable to assess25

Serious8

Not serious

Serious8

Not serious

Not serious9

Serious24

Not serious9

Observational

RCT

Observational

RELATIVE/MEAN DIFFERENCE4 (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER3

IMPRECISION

INDIRECTNESS2

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN1

NO. OF STUDIES/ COHORTS

十十◯◯

LOW

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

十十◯◯

LOW

十十◯◯

LOW

十◯◯◯

VERY LOW

十十◯◯

LOW

100 Health effects of the use of non-sugar sweeteners

CERTAINTY6

Cardiovascular diseases: hypertension

EFFECT

ABSOLUTE – PER 10005 (95% CI)

Cardiovascular diseases: systolic blood pressure (mmHg)

Cardiovascular diseases: diastolic blood pressure (mmHg)

Cardiovascular diseases: LDL-cholesterol (mmol/L)

Cardiovascular diseases: total cholesterol (mmol/L)

Cardiovascular diseases: HDL cholesterol (mmol/L)

Cardiovascular diseases: total cholesterol to HDL cholesterol ratio

Cardiovascular diseases: low HDL cholesterol

Cardiovascular diseases: triglycerides (mmol/L)

46 more

(from 32 more to 60 more)

–

15 more

(from 39 fewer to 78 more)

–

HR 1.13

(1.09 to 1.17)

MD –1.33

(–2.71 to 0.06)

MD –0.51

(–1.68 to 0.65)

MD 0.03

(–0.03 to 0.09)

MD 0.01

(–0.09 to 0.11)

MD 0.00

(–0.03 to 0.03)

MD 0.09

(0.02 to 0.16)

HR 1.03

(0.92 to 1.16)

MD –0.04

(–0.11 to 0.04)

81965/234137 (35%)

602

448

540

511

546

160

5823/11916 (48.9%)

559

838

689

653

567

659

166

684

None

Not serious

Not serious10

Serious14

Not serious10

Serious16

Serious14

Not serious

Serious8

Not serious

Serious8

Not serious9

Serious28

Not serious29

Not serious9

Serious28

Observational

RCT

Observational

RCT

RELATIVE/MEAN DIFFERENCE4 (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER3

IMPRECISION

INDIRECTNESS2

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN1

NO. OF STUDIES/ COHORTS

十十◯◯

LOW

十十十◯

MODERATE

十十十◯

MODERATE

十十◯◯

LOW

十十◯◯

LOW

十十十◯

MODERATE

十十十◯

MODERATE

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

101 Annex 7. GRADE evidence profiles

CERTAINTY6

Cardiovascular diseases: high triglycerides

EFFECT

ABSOLUTE – PER 10005 (95% CI)

Cancer: cancer mortality

Cancer: incidence (any type)

Cancer: incidence (bladder)

Chronic kidney disease: incident disease

Chronic kidney disease: creatinine (μmol/L)

Chronic kidney disease: albumin (g/L)

Energy intake (kJ/day)

Sugars intake (g/day)

16 more

(from 63 fewer to 110 more)

1 more

(from 4 fewer to 6 more)

1 more

(from 1 fewer to 3 more)

–

71 more

(from 19 fewer to 213 more)

–

HR 1.03

(0.88 to 1.21)

HR 1.02

(0.92 to 1.13)

HR 1.02

(0.95 to 1.09)

OR 1.31

(1.06 to 1.62)

HR 1.41

(0.89 to 2.24)

MD 8.80

(–14.65 to 32.25)

MD 0.00

(–0.56 to 0.56)

MD –569

(–859 to –278)

MD –38.4

(–57.8 to –19.1)

6673/12728 (52.4%)

25494/568175 (4.5%)

27573/942600 (2.9%)

11071 cases 28589 controls

3161/18372 (17.2%)

1077

587

1131

652

None

Serious14

Not serious

Serious14

Very serious31

Serious16

Not serious

Serious8

Not serious

Serious8

Not serious

Serious8

Not serious9

Serious11

Not serious9

Serious30

Serious32

Serious33

Observational

Observational
(case-control)

Observational

RCT

RELATIVE/MEAN DIFFERENCE4 (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER3

IMPRECISION

INDIRECTNESS2

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN1

NO. OF STUDIES/ COHORTS

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

十十◯◯

LOW

十十◯◯

LOW

十十◯◯

LOW

102 Health effects of the use of non-sugar sweeteners

BMI: body mass index; CI: confidence interval; HDL: high-density lipoprotein; HOMA-IR: Homeostatic Model Assessment of Insulin Resistance; HR: hazard ratio; LDL: low-density lipoprotein; MD: mean difference; NSS: non-sugar sweeteners; OR: odds ratio; RCT: randomized controlled trial.

1 Unless otherwise noted, observational studies are prospective cohort studies that assessed outcomes by comparing the highest quantile of intake to the lowest. Some cohort studies assessed outcomes continuously, as noted in the evidence profile.
2 All studies were conducted in the population of interest (i.e. general adult population). Although most studies were conducted in North America and Europe, and very few were conducted in low- and middle- income countries (LMICs), physiological responses to NSS are not expected to differ significantly across different populations. Behavioural responses may differ between those who are habituated to sweet- tasting foods and beverages and those whose diets contain little to no sweet foods or beverages. However, in populations with limited exposure to NSS (which may be found more widely in LMICs), the effects observed on the consumption of NSS in this review may be largely irrelevant unless they are introduced to these populations. With the exception of LDL cholesterol, blood lipids, glycaemic markers and blood pressure are largely unvalidated intermediate markers of disease and, although informative, are not a surrogate for disease. However, the WHO NUGAG Subgroup on Diet and Health prioritized intermediate markers in the outcomes of interest and, therefore, none of these outcomes were downgraded for indirectness.
3 Funnel plot analyses conducted for outcomes with 10 studies or more. Unless otherwise noted, funnel plot analysis did not suggest significant risk for publication bias.
4 For observational studies, relative effects are most-adjusted multivariate estimates (i.e. the multivariate association measure with the highest number of covariates as reported in individual studies).
5 Based on the event rate in the studies – that is, the number of people with events divided by the total number of people. The absolute effect (per 1000 people) is calculated using the following equation: absolute

effect = 1000 × [event rate × (1 – RR)]. The magnitude of absolute effect in “real world” settings depends on baseline risk, which can vary across different populations.
6 Critical outcomes in this evidence profile are shown in blue and important outcomes in black, as prioritized by the WHO NUGAG Subgroup on Diet and Health. Outcomes can be assessed as either not important,

important or critical for decision-making in the WHO guideline development process (12).
7 Most RCTs included in the meta-analyses for measures of adiposity were assessed as having unclear risk of bias overall as a result of lack of necessary detail in reporting the methods that were used. Less than

half of the trials for body weight and slightly more than half for BMI appeared to use appropriate methods of random sequence generation (one or two employed inadequate randomization methods). Less than a quarter of the trials reported adequate allocation concealment for body weight and a third for BMI (except for one trial with inadequate allocation concealment of body weight; details in remaining trials were not reported and thus assessed as unclear). Blinding of participants was only possible in one or two studies; it was not possible in half the remaining trials (studies comparing NSS with water or nothing) and unclear in the other half (NSS compared with sugars, because it is unknown to what extent the participants could taste the difference between foods and beverages sweetened with NSS and those sweetened with sugars). Only a very small number of trials provide sufficient information to enable an assessment regarding blinding of outcome assessment. A little fewer than half the trials did not report significant participant dropout or imbalance in dropout rates across arms, and about half of the remaining trials reported significant dropout rates (>15%), which represent a serious concern. However, most trials did not provide sufficient detail regarding reasons for participant dropout, so it is difficult to determine whether attrition might have affected results. Selective reporting of outcomes was clearly evident in only a very small number of trials; of the remaining trials, about half were assessed as low risk of bias and half as unclear risk of bias. No other significant sources of bias were identified. Although most trials appeared to be well conducted, the widespread lack of detail in the reporting of methods creates significant uncertainty regarding risk of bias. Downgraded once as a conservative measure.
8 I2 ≥ 50%, indicating a significant level of heterogeneity. Where the number of studies was sufficient to explore heterogeneity via subgroup and sensitivity analyses, results of the analysis did not significantly explain the observed heterogeneity. Downgraded once.
9 Mean Newcastle–Ottawa Score of >5 with very conservative application of ratings. Not downgraded.
10 A small mean effect, likely of little to no clinical significance, and neither bound of the 95% CI includes a potentially important benefit or harm. Therefore, considered a sufficiently precise estimate of no effect.

Not downgraded.
11 Mean Newcastle–Ottawa Score of ≤5 with very conservative application of ratings. Downgraded once.
12 One bound of the 95% CI includes potentially important benefit or harm and the other bound crosses the null in the opposite direction, but only very slightly and as a result of the outlying effect in one study

(25). In sensitivity analysis in which the study is removed, the upper bound no longer crosses the null. Not downgraded.
13 The sample size is relatively small for prospective cohort studies, but sufficiently large and with a high event rate. Not downgraded.
14 One bound of the 95% CI includes potentially important benefit or harm and the other bound crosses the null in the opposite direction, and/or the sample size is small. Downgraded once.
15 Only one trial was assessed as having adequately randomized and maintained allocation concealment (others unclear). One trial was an abstract only with overall high risk of bias. Remaining domains for the

other two trials were assessed as half with low risk of bias and half with unclear risk. Downgraded once.
16 A small mean effect, likely of little to no clinical significance, and neither bound of the 95% CI includes a potentially important benefit or harm. However, the sample size is small. Downgraded once.
17 All but one trial had adequate randomization, and nearly half had adequate allocation concealment (the remainder were unclear). One trial had incomplete data, and another concerns about selective reporting.

Six trials could not blind participants, and it was unclear if participants were blinded in the other two. The remaining domains were approximately half with low risk of bias and half unclear. Not downgraded.
18 The majority of trials had adequate randomization, but only one or two had adequate allocation concealment (the remainder were unclear). Two trials had incomplete data. Two trials could not blind participants, and it was unclear if participants were blinded in the remaining trials. For fat mass (%), there were concerns in one trial about selective reporting. The remaining domains were approximately half with low risk

of bias and half unclear. Not downgraded.

103 Annex 7. GRADE evidence profiles

19 Six out of the 10 comparisons that reported a Ptrend reported a Ptrend of <0.05, suggestive of a dose–response relationship within those individual studies. However, as a conservative measure, it was not upgraded. Funnel plot analysis suggested slight possibility of publication bias, but not of significant concern. Not downgraded.
20 Slightly more than half the trials had adequate randomization, and one had inadequate randomization. Only four of the trials had adequate allocation concealment (the remainder were unclear). More than half the trials could not blind participants to treatment. Two trials had incomplete data, and there were concerns about selective reporting in two trials (one trial had both). One trial was an abstract only with overall high risk of bias. The remaining domains were approximately half with low risk of bias and half unclear. Downgraded once.
21 In these trials, the majority had adequate randomization, and one had inadequate randomization. Half had adequate allocation concealment (the remainder were unclear). Slightly more than half the trials could not blind participants to treatment. One trial had incomplete data. The remaining domains were approximately half with low risk of bias and half unclear. Not downgraded.
22 In these trials, the majority had adequate randomization, and half had adequate allocation concealment (the remainder were unclear). Half the trials could not blind participants to treatment. One trial had incomplete data, and one had concerns about selective reporting. One trial was an abstract only with overall high risk of bias. The remaining domains were approximately half with low risk of bias and half unclear. Not downgraded.
23 Fewer than half the trials had adequate randomization, and one had inadequate randomization. Only four of the trials had adequate allocation concealment (the remainder were unclear). More than half the trials could not blind participants to treatment. Two trials had incomplete data. The remaining domains were approximately half with low risk of bias and half unclear. Downgraded once.
24 This single study had adequate randomization but insufficient information to assess allocation concealment, blinding of outcome assessment or selective reporting. It was at high risk of bias for blinding of participants and incomplete data. Downgraded once.
25 Unable to assess inconsistency in a single study. Downgraded once.
26 Extremely small sample size. Downgraded twice.
27 The data for dental caries were reported in the original publication of this trial, Maersk et al. (2012) (183).
28 The majority of trials had adequate randomization, but fewer than half had adequate allocation concealment (the remainder were unclear). A significant number of trials could not blind participants, and it was

unclear if participants were blinded in the remaining trials. One or two trials trial had incomplete data, and there were concerns in 1–3 trials about selective reporting. One or two of the trials for most outcomes

were abstract only and of high risk of bias overall. The remaining domains were approximately half with low risk of bias and half unclear. Downgraded once.
29 The majority of trials had adequate randomization, but only one had adequate allocation concealment (the remainder were unclear). Only one trial could not blind participants. The remaining domains were

approximately half with low risk of bias and half unclear. Not downgraded.
30 One trial was fairly well reported, and the other was mostly unclear, with concerns about selective reporting of outcomes. Downgraded once.
31 The 95% CI crosses the null and includes both significant benefit and harm. Downgraded twice.
32 A little fewer than half the trials had adequate randomization, and about a quarter had adequate allocation concealment (the remainder were unclear). One trial was at high risk of bias for both inadequate

randomization and allocation concealment. Half the trials could not blind participants and it was unclear if participants were blinded in all but two of the remaining trials. Eight trials had incomplete data, and

there were concerns in one trial about selective reporting. The remaining domains were approximately half with low risk of bias and half unclear. Downgraded once.
33 A third of the trials had adequate randomization, and one had adequate allocation concealment (the remainder were unclear). One trial was at high risk of bias for both inadequate randomization and allocation concealment. More than half the trials could not blind participants, and it was unclear if participants were blinded in all but one of the remaining trials. Three trials trial had incomplete data. The remaining

domains were more low risk of bias than unclear, but not by a significant margin. Downgraded once.

104 Health effects of the use of non-sugar sweeteners

CERTAINTY3

Adiposity: body weight (kg)

EFFECT

ABSOLUTE – PER 1000 (95% CI)

Adiposity: BMI (kg/m2)

–

MD –0.61

(–1.28 to 0.06)

MD –0.01

(–0.38 to 0.35)

236

180

361

286

None

Serious5

Not serious

Not serious4

RCT

RELATIVE/MEAN DIFFERENCE (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER2

IMPRECISION

INDIRECTNESS1

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN

NO. OF STUDIES/ COHORTS

GRADE evidence profile 2 Question: What is the effect of replacing sugars with non-sugar sweeteners in adults? Population: General adult population

BMI: body mass index; CI: confidence interval; MD: mean difference; NSS: non-sugar sweeteners; RCT: randomized controlled trial.

十十十◯

MODERATE

十十十◯

MODERATE

1 All studies were conducted in the population of interest (i.e. general adult population). Although most studies were conducted in North America and Europe, and very few were conducted in low- and middle- income countries (LMICs), physiological responses to NSS are not expected to differ significantly across different populations. Behavioural responses may differ between those who are habituated to sweet- tasting foods and beverages and those whose diets contain little to no sweet foods or beverages. However, in populations with limited exposure to NSS (which may be found more widely in LMICs), the effects observed on the consumption of NSS in this review may be largely irrelevant unless they are introduced to these populations. With the exception of LDL cholesterol, blood lipids, glycaemic markers and blood pressure are largely unvalidated intermediate markers of disease and, although informative, are not a surrogate for disease. However, the WHO NUGAG Subgroup on Diet and Health prioritized intermediate markers in the outcomes of interest and therefore, none of these outcomes were downgraded for indirectness.
2 Too few studies to conduct funnel plot analyses.
3 Both outcomes are critical outcomes as prioritized by the WHO NUGAG Subgroup on Diet and Health. Outcomes can be assessed as either not important, important or critical for decision-making in the WHO

guideline development process (12).
4 Half the trials had adequate randomization, but most lacked sufficient detail to assess whether allocation concealment was adequate (unclear risk of bias). Three of the four trials could not blind participants to

treatment. There were no other significant sources of bias. Not downgraded.
5 One bound of the 95% CI includes potentially important benefit or harm and the other bound crosses the null in the opposite direction, and/or the sample size is small. Downgraded once.

105 Annex 7. GRADE evidence profiles

CERTAINTY4

Adiposity: body weight (kg)

EFFECT

ABSOLUTE – PER 1000 (95% CI)

Adiposity: BMI (kg/m2)

Adiposity: BMI z score

Adiposity: waist circumference (cm)

Adiposity: fat mass (kg)

Adiposity: fat mass (%)

–

MD –1.01

(–1.54 to –0.48)

MD 0.03

(–0.14 to 0.21)

MD 0.08

(–0.01 to 0.17)

MD 0.04

(–0.32 to 0.40)

MD –0.07

(–0.26 to 0.11)

MD –0.23

(–0.70 to 0.25)

MD 0.00

(–0.30 to 0.30)

MD –0.66

(–1.23 to –0.09)

MD –0.57

(–1.02 to –0.12)

MD –1.00

(–2.52 to 0.52)

MD –1.07

(–1.99 to –0.15)

MD –1.53

(–5.73 to 2.66)

322

1633

11907

2426

840

610

322

720

319

424

319

None

Not serious

Not serious8

Serious10

Not serious

Serious10

Not serious

Serious10

Not serious

Serious13

Not serious

Serious13

Not serious

Unable to assess6

Not serious

Serious9

Not serious

Serious9

Unable to
assess6

Serious9

Not serious5

Not serious7

Not
serious7

Not
serious11

Not
serious7

Serious12

Not
serious5

Serious12

Not
serious5

Not
serious7

RCT

Observational (continuous)

Observational
(continuous)

Observational
(high vs low)

RCT

Observational
(continuous)

Observational
(high vs low)

RCT

Observational

RCT

Observational

RELATIVE/MEAN DIFFERENCE (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER3

IMPRECISION

INDIRECTNESS2

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN1

NO. OF STUDIES/ COHORTS

GRADE evidence profile 3 Question: What is the effect of higher vs lower intake of non-sugar sweeteners in children? Population: General child population

1
2

5
2

2
3
1

1
1

1
2

十十十◯

MODERATE

十十◯◯

LOW

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

十十十◯

MODERATE

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

十十十◯

MODERATE

十十十◯

MODERATE

十◯◯◯

VERY LOW

十十十◯

MODERATE

十◯◯◯

VERY LOW

106 Health effects of the use of non-sugar sweeteners

CERTAINTY4

Adiposity: incident overweight

EFFECT

ABSOLUTE – PER 1000 (95% CI)

Diabetes: intermediate markers

Dental caries

19 more

(from 44 fewer to 205 more)

In this cohort of 12–18-year-old overweight children followed up for 1 year, chronic consumers of NSS-sweetened beverages had no difference in intermediate markers of diabetes when compared with NSS-sweetened beverage initiators and non- consumers, except for HbA1c, which increased more in chronic consumers of NSS-sweetened beverages (P = 0.01) (193).

Unable to meta-analyse

In one trial, snacks containing stevia or sugars were given twice daily to children for 6 weeks. At the end of the trial, in the stevia arm, the concentrations of cariogenic bacteria Streptococcus mutans and lactobacilli (χ2 = 8.01; P < 0.01) and the probability of developing caries (measured by a cariogram) decreased compared with baseline, whereas there were no statistically significant changes in the sugars arm (209).

In another trial, mouth rinse containing stevia or placebo was used daily by children for 6 months. At the end of the trial, there was a significant improvement in the stevia arm compared with the placebo group in plaque scores (P = 0.03) and gingival scores (P = 0.01). There were no changes in the number of cavitated lesions in the stevia arm, but there was an increase in cavitated lesions in the placebo arm (from 5.6% to 5.8%) (210).

OR 1.25

(0.43 to 3.66)

235/3064 (7.7%)

116

115

None

Very serious14

Serious10

Not serious

Serious14

Not serious

Unable to assess6

Unable to
assess16

Not serious7

Serious12

Not
serious15

Observational

RCT

RELATIVE/MEAN DIFFERENCE (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER3

IMPRECISION

INDIRECTNESS2

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN1

NO. OF STUDIES/ COHORTS

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

2 十十◯◯ LOW

107 Annex 7. GRADE evidence profiles

CERTAINTY4

Dental caries (continued)

EFFECT

ABSOLUTE – PER 1000 (95% CI)

Cardiovascular diseases: blood lipids

Cancer: brain cancer

Energy intake (kJ/day)

This prospective cohort study found that low intakes of NSS-sweetened beverages were associated with fewer teeth surfaces having caries compared with no intake (P < 0.025). However, the association with high intakes of NSS-sweetened beverages was not reported (211).

In this cohort of 12–18-year-old overweight children followed up for 1 year, chronic consumers of NSS-sweetened beverages had no difference in total, HDL and LDL cholesterol, and triglycerides when compared with NSS-sweetened beverage initiators and non-consumers (193).

2 more

(from 2 fewer to 7 more)

In this trial, the energy intake of children receiving drinks with sugars was 419 kJ/day higher than in those receiving drinks with NSS (190).

Unable to meta-analyse

In one cohort study, energy intake in those who initiated consuming NSS-sweetened beverages was 432 kJ/day higher and in chronic/existing consumers of NSS-sweetened beverages was 2462 kJ/day higher than in those who did not consume NSS-sweetened beverages after 1 year of follow-up (193).

In the second cohort study, energy intake was 122 kJ/day higher per 100 g/day increase in NSS- sweetened beverage consumption (200).

OR 1.14

(0.80 to 1.63)

642

371 cases 780 controls

187

173 (cohort 1) 2371 (cohort 2)

199

None

Unable to assess17

Serious10

Unable to
assess17

Not serious

Serious14

Not serious

Unable to assess6

Not serious

Unable to
assess6

Unable to
assess17

Serious12

Not
serious18

Serious12

Observational

Observational
(case-control)

RCT

Observational

RELATIVE/MEAN DIFFERENCE (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER3

IMPRECISION

INDIRECTNESS2

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN1

NO. OF STUDIES/ COHORTS

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

十十十◯

MODERATE

十◯◯◯

VERY LOW

108 Health effects of the use of non-sugar sweeteners

CERTAINTY4

Sugars intake (g/day)

EFFECT

ABSOLUTE – PER 1000 (95% CI)

Neurocognition

Unable to meta-analyse

In one cohort study, chronic users of NSS- sweetened beverages had a 40.2 g/day (SE 11.6) higher sugars intake than never users, whereas initiators of NSS-sweetened beverages had a 23.9 g/day (SE 17.9) lower sugars intake than never users (193).

In a second cohort study, sugars intake was not associated with NSS-sweetened beverage intake (200).

In an RCT, children were given drinks with sucralose or sucrose for 8.5 months. There were no significant differences between the two arms in cognition measures (tested using the Kaufman Assessment Battery for Children version II [KABC- II] subtests and the Hopkins Verbal Learning Test [HVLT]) (190).

In a cohort study following children in utero up to 7 years of age, early- and mid-childhood cognition scores were not associated with childhood intake of NSS-sweetened beverages at 3 years (215).

173 (cohort 1) 2371 (cohort 2)

199

1234

200

None

Unable to assess17

Serious10

Unable to assess17

Not serious

Unable to assess17

Unable to assess6

Unable to
assess6

Serious12

Not
serious18

Not
serious7

Observational

RCT

Observational

RELATIVE/MEAN DIFFERENCE (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER3

IMPRECISION

INDIRECTNESS2

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN1

NO. OF STUDIES/ COHORTS

十◯◯◯

VERY LOW

十十◯◯

LOW

十◯◯◯

VERY LOW

BMI: body mass index; CI: confidence interval; HDL: high-density lipoprotein; LDL: low-density lipoprotein; MD: mean difference; OR: odds ratio; NSS: non-sugar sweeteners; RCT: randomized controlled trial; SE: standard error.

1 Unless otherwise noted, observational studies are prospective cohort studies that assessed outcomes by comparing the highest quantile of intake to the lowest. Some cohort studies assessed outcomes continuously, as noted in the evidence profile.
2 Unless otherwise noted, all studies were conducted in the population of interest (i.e. general child population). Although most studies were conducted in North America and Europe, and very few were conducted in low- and middle-income countries (LMICs), physiological responses to NSS are not expected to differ significantly across different populations. Behavioural responses may differ between those who are habituated to sweet-tasting foods and beverages and those whose diets contain little to no sweet foods or beverages. However, in populations with limited exposure to NSS (which may be found more widely in LMICs), the effects observed on the consumption of NSS in this review may be largely irrelevant unless they are introduced to these populations.
3 Too few studies to conduct funnel plot analyses.
4 Critical outcomes in this evidence profile are shown in blue and important outcomes in black, as prioritized by the WHO NUGAG Subgroup on Diet and Health. Outcomes can be assessed as either not important,

important or critical for decision-making in the WHO guideline development process (12).

109 Annex 7. GRADE evidence profiles

5 This single RCT was well conducted, with adequate randomization and allocation concealment. There was a high attrition rate, with more than 20% of participants dropping out; however, imputation of missing values suggested no imbalance in arms with or without missing participants. Not downgraded.
6 Unable to assess inconsistency as there is only a single study. Downgraded once.
7 Mean Newcastle–Ottawa Score of >5 with very conservative application of ratings. Not downgraded.
8 A small mean effect, likely of little to no clinical significance, and neither bound of the 95% CI includes a potentially important benefit or harm. Therefore, considered a sufficiently precise estimate of no effect.

Not downgraded
9 I2 ≥ 50%, indicating a significant level of heterogeneity. Downgraded once.
10 One bound of the 95% CI includes potentially important benefit or harm and the other bound crosses the null in the opposite direction, and/or the sample size is small. Downgraded once.
11 These RCTs were well conducted, although for one it was unclear whether it was adequately randomized. Both had adequate allocation concealment. There was a high attrition rate, with more than 20% of

participants dropping out of one trial; however, imputation of missing values suggested no imbalance in arms with or without missing participants. No other sources of significant bias noted. Not downgraded.
12 Mean Newcastle–Ottawa Score of ≤5 with very conservative application of ratings. Downgraded once.
13 This single, very small cohort was conducted exclusively in overweight Hispanic adolescents. As evidence from this review suggests that people with overweight and/or obesity may respond differently to the

use of NSS from people of normal weight, this cohort may not be an adequate representation of the general child population. Downgraded once, together with inconsistency.
14 The 95% CI crosses the null and includes both significant benefit and harm. Downgraded twice.
15 Neither trial included sufficient information to assess whether randomization was adequate, but both had adequate allocation concealment, and other domains were mostly assessed as low risk of bias. Not

downgraded.
16 Unable to assess inconsistency as there only two studies which could not be meta-analysed, although both report lower risk of caries with NSS. Downgraded once as a conservative measure.
17 Unable to assess. Downgraded once.
18 It was unclear whether this single, well-conducted trial was adequately randomized, but other domains – save for blinding of participants (unclear) – were assessed as low risk of bias. Not downgraded.

110 Health effects of the use of non-sugar sweeteners

CERTAINTY3

Gestational diabetes

EFFECT

ABSOLUTE – PER 1000 (95% CI)

Preterm birth

Birth weight

5 fewer

(from 12 fewer to 0 more)

12 more

(from 3 more to 23 more)

Unable to meta-analyse

In a cohort analysis of the German GeliS trial, the daily intake of light drinks during pregnancy was associated nonsignificantly with growth measures in the child at birth (birthweight – adjusted regression coefficient –5; 95% CI -18, 6; BMI at birth – adjusted regression coefficient 0.005; 95% CI –0.020, 0.035; low birthweight – adjusted OR 0.99; 95% CI 0.91, 1.08; small for gestational age – adjusted OR 1.03; 95% CI 0.98, 1.09; and large for gestational age – adjusted OR 1.01; 95% CI 0.85, 1.07) (223).

In a Dutch cohort of pregnant women, intake of NSS-sweetened products before conception was associated with increased birthweight (adjusted z-score coefficient per 10 g per 1000 kcal/day: 0.001; 95% CI 0.000, 0.001; P = 0.002) (224).

In a cohort study with women with gestational diabetes in Slovenia, intake of low-calorie beverages9 was not associated with large for gestational age (Spearman correlation 0.118; P nonsignificant) (225).

RR 0.92

(0.81 to 1.04)

OR 1.25

(1.07 to 1.46)

860/13475 (6.4%)

6381/129009 (4.9%)

3716

None

Serious6

Not serious

Unable to assess8

Not serious

Unable to assess5

Not serious

Unable to
assess5

Not serious4

Serious7

Observational

RELATIVE/MEAN DIFFERENCE (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER2

IMPRECISION

INDIRECTNESS1

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN

NO. OF STUDIES/ COHORTS

GRADE evidence profile 4 Question: What is the effect of higher vs lower intake of non-sugar sweeteners in pregnant women? Population: Pregnant women

十◯◯◯

VERY LOW

十十◯◯

LOW

十◯◯◯

VERY LOW

111 Annex 7. GRADE evidence profiles

CERTAINTY3

Offspring adiposity

EFFECT

ABSOLUTE – PER 1000 (95% CI)

Offspring asthma

Offspring allergies

Unable to meta-analyse

In a prospective cohort study of pregnant women conducted in Canada, the daily intake of NSS-sweetened beverages during pregnancy (compared with less than 1 serving per month) was associated with a 0.2 increase in infant BMI z-score (95% CI 0.02, 0.38) and a more than twofold increase in risk of overweight at 1 year of age (adjusted OR 2.19; 95% CI 1.23, 3.88). Adjustment was made for maternal BMI, diet quality, total energy intake and other obesity risk factors (226).

In a prospective cohort study conducted in the United States, consumption of NSS-sweetened beverages during pregnancy was not associated with BMI z-score or waist circumference in offspring at mid-childhood (median of 7.7 years of age) (227).

In a prospective cohort study conducted in Denmark, the children of women with gestational diabetes who consumed NSS-sweetened beverages at ≥1/day (compared with never) had a higher BMI z-score (b 0.59; 95% CI 0.23, 0.96) and risk of overweight or obesity (RR 1.93; 95% CI 1.24, 3.01) at 7 years of age (228).

10 more

(from 3 more to 17 more)

5 more

(from 7 fewer to 21 more)

OR 1.20

(1.07 to 1.35)

OR 1.11

(0.86 to 1.43)

5029

1536/31849 (4.8%)

1855/37971 (4.9%)

None

Unable to assess8

Not serious

Serious6

Not serious

Unable to assess5

Unable to
assess5

Not serious4

Observational

RELATIVE/MEAN DIFFERENCE (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER2

IMPRECISION

INDIRECTNESS1

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN

NO. OF STUDIES/ COHORTS

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

十◯◯◯

VERY LOW

112 Health effects of the use of non-sugar sweeteners

CERTAINTY3

Offspring neurocognition

EFFECT

ABSOLUTE – PER 1000 (95% CI)

In a prospective cohort study following children in utero up to 7 years of age, early- and mid- childhood cognition scores were inversely associated with maternal intake of NSS- sweetened beverages during pregnancy (PPVT- III, early childhood: –1.2; 95% CI –2.9, 0.5; total WRAVMA, early childhood: –1.5; 95% CI –2.9, –0.1; KBIT-II verbal, mid-childhood: –3.2; 95% CI –5.0, –1.5; KBIT-II nonverbal, mid-childhood: –2.0; 95% CI –4.3, 0.2; WRAVMA drawing, mid- childhood: –1.7; 95% CI –4.1, 0.6; WRAML visual memory, mid-childhood: –0.1; 95% CI –0.7, 0.5), but not with childhood intake of NSS-sweetened beverages at 3 years (215).

1234

None

Unable to assess8

Not serious

Unable to assess5

Not serious4

Observational

RELATIVE/MEAN DIFFERENCE (95% CI)

NO. OF EVENTS/PARTICIPANTS (STUDY EVENT RATE)

HIGHER NSS INTAKE

LOWER/NO NSS INTAKE

ASSESSMENT

OTHER2

IMPRECISION

INDIRECTNESS1

INCONSISTENCY

RISK OF BIAS

STUDY DESIGN

NO. OF STUDIES/ COHORTS

十◯◯◯

VERY LOW

BMI: body mass index; CI: confidence interval; KBIT-II, Kaufman Brief Intelligence Test 2nd edition; OR: odds ratio; PPVT-III: Peabody Picture Vocabulary Test-III; NSS: non-sugar sweeteners; OR: odds ratio; RR: relative risk; WRAML: Wide Range Assessment of Memory and Learning; WRAVMA: Wide Range Assessment of Visual Motor Ability.

1 All studies were conducted in the population of interest (i.e. general population of pregnant women). Although most studies were conducted in North America and Europe, and very few were conducted in low- and middle-income countries (LMICs), physiological responses to NSS are not expected to differ significantly across different populations. Behavioural responses may differ between those who are habituated to sweet-tasting foods and beverages and those whose diets contain little to no sweet foods or beverages. However, in populations with limited exposure to NSS (which may be found more widely in LMICs), the effects observed on the consumption of NSS in this review may be largely irrelevant unless they are introduced to these populations.
2 Too few studies to conduct funnel plot analyses.
3 Outcomes specific to pregnancy were not prioritized by the WHO NUGAG Subgroup on Diet and Health, and therefore there is no designation as critical or important.
4 Mean Newcastle–Ottawa Score of >5 with very conservative application of ratings. Not downgraded.
5 Unable to assess inconsistency as there is only a single study, or a small number of studies that could not be meta-analysed. Downgraded once.
6 One bound of the 95% CI includes potentially important benefit or harm and the other bound crosses the null in the opposite direction, and/or the sample size is small. Downgraded once.
7 Mean Newcastle–Ottawa Score of ≤5 with very conservative application of ratings. Downgraded once.
8 Unable to assess. Downgraded once.
9 Based on the reporting of other beverage types in this study, it was determined that “low-calorie beverages” consisted primarily, if not entirely, of NSS-sweetened beverages.

113 Annex 7. GRADE evidence profiles

ANNEX 8.

Funnel plots

Fig. A8.1 Body weight (kg) among adults in randomized controlled trials

114 Health effects of the use of non-sugar sweeteners

Fig. A8.2. Body mass index (kg/m2) among adults in randomized controlled trials

Fig. A8.3 Fasting glucose (mmol/L) among adults in randomized controlled trials

115 Annex 8. Funnel plots

Fig. A8.4 Type 2 diabetes among adults in cohort studies

Fig. A8.5 Funnel plot of HOMA-IR among adults in randomized controlled trials

116 Health effects of the use of non-sugar sweeteners

Fig. A8.6 Systolic blood pressure (mmHg) among adults in randomized controlled trials

Fig. A8.7 Diastolic blood pressure (mmHg) among adults in randomized controlled trials

117 Annex 8. Funnel plots

Fig. A8.8 LDL cholesterol (mmol/L) among adults in randomized controlled trials

Fig. A8.9 HDL cholesterol (mmol/L) among adults in randomized controlled trials

118 Health effects of the use of non-sugar sweeteners

Fig. A8.10 Bladder cancer among adults in case–control studies

Fig. A8.11 Energy intake (kJ/day) among adults in randomized controlled trials

119 Annex 8. Funnel plots

Fig. A8.12 Sugars intake (g/day) among adults in randomized controlled trials

120 Health effects of the use of non-sugar sweeteners

ANNEX 9.

Supplementary figures

Fig. A9.1

Effect of NSS on waist circumference (cm) in randomized controlled trials in adults

Fig. A9.2

Effect of NSS on waist-to-hip ratio in randomized controlled trials in adults

Fig. A9.3

Effect of NSS on fat mass (kg) in randomized controlled trials in adults

121 Annex 9. Supplementary figures

Fig. A9.4

Effect of NSS on fat mass (%) in randomized controlled trials in adults

Fig. A9.5

Effect of NSS on lean mass (kg) in randomized controlled trials in adults

Fig. A9.6

Association between NSS and body weight (kg) in prospective cohort studies (continuous effect) in adults

122 Health effects of the use of non-sugar sweeteners

Fig. A9.7

Association between NSS and body weight (kg) in prospective cohort studies (highest versus lowest) in adults

Fig. A9.8

Association between NSS and waist circumference (cm) in cohort studies (highest versus lowest) in adults

Fig. A9.9

Association between NSS and abdominal obesity in cohort studies (highest versus lowest) in adults

123 Annex 9. Supplementary figures

Fig. A9.10 Meta-regression: body weight results in randomized controlled trials by study duration

Note: B coefficient = –0.002; P = 0.052.

124 Health effects of the use of non-sugar sweeteners

Fig. A9.11 Effect of NSS on body weight (kg) in randomized controlled trials, subgrouped by study duration, in adults

125 Annex 9. Supplementary figures

Fig. A9.12 Effect of NSS on body mass index (kg/m2) in randomized controlled trials, subgrouped by consumption pattern, in adults

126 Health effects of the use of non-sugar sweeteners

Fig. A9.13 Meta-regression: body weight by energy intake in randomized controlled trials

Note: B coefficient = 0.008; P = 0.009.

127 Annex 9. Supplementary figures

Fig. A9.14 Meta-regression: body mass index by energy intake in randomized controlled trials

Note: B coefficient = 0.0003; P < 0.001.

128 Health effects of the use of non-sugar sweeteners

Fig. A9.15 Effect of NSS on body weight (kg) in randomized controlled trials, subgrouped by type of NSS, in adults

129 Annex 9. Supplementary figures

Fig. A9.16 Effect of NSS on body weight (kg) in randomized controlled trials, subgrouped by delivery mode, in adults

130 Health effects of the use of non-sugar sweeteners

Fig. A9.17 Effect of NSS intake on body weight (kg) in randomized controlled trials, subgrouped by consumption pattern

131 Annex 9. Supplementary figures

Fig. A9.18 Effect of NSS on body mass index (kg/m2) in randomized controlled trials, subgrouped by weight status, in adults

132 Health effects of the use of non-sugar sweeteners

Fig. A9.19 Effect of NSS on body mass index (kg/m2) in randomized controlled trials, subgrouped by delivery mode, in adults

133 Annex 9. Supplementary figures

Fig. A9.20 Effect of NSS on body mass index (kg/m2), subgrouped by study design (weight loss studies versus non–weight loss studies), in adults

Note: Weight loss studies were those in which the participants were instructed to restrict energy intake AND consume NSS or control. Weight maintenance studies were those that followed up participants after active weight loss, with instructions on energy intake designed to prevent weight gain. Non–weight loss studies were those that had no intentional weight loss component.

134 Health effects of the use of non-sugar sweeteners

Fig. A9.21 Effect of NSS intake on body mass index (kg/m2), subgrouped by NSS type

135 Annex 9. Supplementary figures

Fig. A9.22

Effect of NSS on body weight (kg) in nonrandomized controlled trials in adults

Fig. A9.23

Effect of NSS on fasting glucose (mmol/L) in randomized controlled trials in adults

Fig. A9.24

Effect of NSS on fasting insulin (pmol/L) in randomized controlled trials in adults

136 Health effects of the use of non-sugar sweeteners

Fig. A9.25

Effect of NSS on HbA1c (%) in randomized controlled trials in adults

Fig. A9.26

Effect of NSS on HOMA-IR in randomized controlled trials in adults

Fig. A9.27

Association between NSS and high fasting glucose in cohort studies (highest versus lowest) in adults

Note: High fasting glucose is defined as ≥5.5 mmol/L.

137 Annex 9. Supplementary figures

Fig. A9.28

Association between NSS and haemorrhagic stroke in cohort studies (highest versus lowest) in adults

Fig. A9.29

Association between NSS and ischaemic stroke in cohort studies (highest versus lowest) in adults

Fig. A9.30

Effect of NSS on total:HDL cholesterol in randomized controlled trials in adults

138 Health effects of the use of non-sugar sweeteners

Fig. A9.31 Effect of NSS on total cholesterol (mmol/L) in randomized controlled trials in adults

Fig. A9.32 Effect of NSS on HDL cholesterol (mmol/L) in randomized controlled trials in adults

139 Annex 9. Supplementary figures

Fig. A9.33 Association between NSS and low HDL cholesterol in cohort studies (highest versus lowest) in adults

Note: Low HDL cholesterol is defined as ≥5.5 mmol/L.

Fig. A9.34 Association between NSS and high triglycerides in cohort studies (highest versus lowest) in adults

Note: High triglycerides are defined as ≥1.70 mmol/L.

140 Health effects of the use of non-sugar sweeteners

Fig. A9.35 Association between NSS and bladder cancer in case–control studies, subgrouped by mode of delivery, in adults

141 Annex 9. Supplementary figures

Fig. A9.36 Association between NSS and bladder cancer in case–control studies, subgrouped by NSS type, in adults

Note: Some studies appear more than once because they had multiple arms (comparing different NSS with a control); therefore, the overall pooled effect is also slightly different from the main effect, and only effects for individual subgroups should be considered.

142 Health effects of the use of non-sugar sweeteners

Fig. A9.37

Association between NSS and brain cancer in case–control studies in adults

Fig. A9.38

Association between NSS and breast cancer in case–control studies in adults

Fig. A9.39

Association between NSS and breast cancer in prospective cohort studies in adults

Fig. A9.40

Association between NSS and colorectal cancer in case–control studies in adults

143 Annex 9. Supplementary figures

Fig. A9.41

Association between NSS and colorectal cancer in prospective cohort studies in adults

Fig. A9.42

Association between NSS and renal cancer in case–control studies in adults

Fig. A9.43

Association between NSS and lung cancer in case–control studies in adults

Fig. A9.44

Association between NSS and pancreatic cancer in case–control studies in adults

144 Health effects of the use of non-sugar sweeteners

Fig. A9.45

Association between NSS and pancreatic cancer in prospective cohort studies in adults

Fig. A9.46

Association between NSS and prostate cancer in case–control studies in adults

Fig. A9.47

Association between NSS and prostate cancer in prospective cohort studies in adults

Fig. A9.48

Association between NSS and gastric cancer in case–control studies in adults

145 Annex 9. Supplementary figures

Fig. A9.49

Association between NSS and leukaemia in cohort studies in adults

Fig. A9.50

Association between NSS and multiple myeloma in cohort studies in adults

Fig. A9.51

Association between NSS and non-Hodgkin lymphoma in cohort studies in adults

146 Health effects of the use of non-sugar sweeteners

Fig. A9.52 Association between NSS and chronic kidney disease in cohort studies in adults

Note: Lin 2011 reported the association between NSS use and decline in estimated glomerular filtration rate (eGFR) of ≥30% (173), and Rebholz 2017, the association between NSS use and chronic kidney disease with one defining characteristic being a ≥25% decline in eGFR (174). Lin 2011 reported the association as an odds ratio which was converted to hazard ratio for this analysis using standard methods as described (16).

Fig. A9.53 Effect of NSS on creatinine (mmol/L) in randomized controlled trials in adults

Fig. A9.54 Effect of NSS on albumin (g/L) in randomized controlled trials in adults

147 Annex 9. Supplementary figures

Fig. A9.55 Effect of NSS on energy intake (kJ/d) in randomized controlled trials, subgrouped by consumption pattern, in adults

148 Health effects of the use of non-sugar sweeteners

Fig. A9.56 Effect of NSS on energy intake (kJ/d) in randomized controlled trials, subgrouped by delivery mode, in adults

149 Annex 9. Supplementary figures

Fig. A9.57 Effect of NSS on energy intake (kJ/d) in randomized controlled trials, subgrouped by study design (weight loss studies versus non–weight loss studies), in adults

150 Health effects of the use of non-sugar sweeteners

Fig. A9.58 Effect of NSS on energy intake (kJ/d) in randomized controlled trials, subgrouped by NSS type, in adults

151 Annex 9. Supplementary figures

Fig. A9.59

Effect of NSS on hunger in randomized controlled trials in adults

Fig. A9.60

Effect of NSS on satiety in randomized controlled trials in adults

Fig. A9.61

Effect of NSS on appetite/desire to eat in randomized controlled trials in adults

152 Health effects of the use of non-sugar sweeteners

Fig. A9.62 Effect of NSS on sugars intake (g/day) in randomized controlled trials, subgrouped by consumption pattern, in adults

153 Annex 9. Supplementary figures

Fig. A9.63 Effect of NSS on sugars intake (g/day) in randomized controlled trials, subgrouped by delivery mode, in adults

154 Health effects of the use of non-sugar sweeteners

Fig. A9.64 Effect of NSS on sugars intake (g/day) in randomized controlled trials, subgrouped by NSS type, in adults

155 Annex 9. Supplementary figures

Fig. A9.65

Effect of NSS on sugars intake (g/day) in randomized controlled trials, subgrouped by study design (weight loss studies versus non–weight loss studies), in adults

Fig. A9.66

Association between NSS and body weight (kg) in cohort studies (continuous) in children

Fig. A9.67

Association between NSS and body mass index (kg/m2) in cohort studies (continuous) in children

156 Health effects of the use of non-sugar sweeteners

Fig. A9.68

Association between NSS and body mass index (kg/m2) in cohort studies (higher versus lower) in children

Fig. A9.69

Effect of NSS on BMI z-score in randomized controlled trials in children

Fig. A9.70

Association between NSS and BMI z-score in cohort studies (continuous) in children

Fig. A9.71

Association between NSS and body fat mass (%) in cohort studies in children

157 Annex 9. Supplementary figures

Fig. A9.72 Association between NSS and overweight in cohort studies in children

Fig. A9.73 Association between NSS and brain cancer in cohort studies in children

158 Health effects of the use of non-sugar sweeteners

ANNEX 10.

Excluded studies

Afonso 2013 (376)
Aguero 2019 (377)
Ahmad 2020 (378)
Ahmad 2020b (379) Akhavan 2011 (380)
Ali 2017 (381)
Alsubaie 2017 (382) Alviso-Orellana 2018 (383) Anonymous 2015 (384) Anonymous 2016 (385) Anonymous 2019 (386) Appelhans 2013 (387) Appelhans 2017 (388) Armstrong 1974 (389) Barraj 2020 (390) Barriocanal 2008 (391) Bawa 2018 (392)

Bawadi 2019 (393)
Beck 2017 (394)
Bellisle 2001 (395)
Bolt-Evensen 2018 (396)
Cancer Prevention Study I 1992 (397) Chen 2021 (398) ChiCTR-IOR-17011657 2017 (399) Cohen 1978 (400)

Conway 2017 (401) Conway 2021 (402) Creighton 2014 (403) Creze 2018 (404)
Cros 2020 (405)
Cullen 2004 (406)
De Christopher 2018 (407)

Wrong study population Wrong study/publication type Wrong intervention/exposure Wrong or no comparator Study duration too short Duplicate
Wrong intervention/exposure Wrong intervention/exposure Wrong study/publication type Wrong study/publication type Wrong study/publication type Wrong intervention/exposure Wrong intervention/exposure Wrong study/publication type No outcome of interest
NSS too high
Wrong intervention/exposure Wrong intervention/exposure Wrong intervention/exposure Wrong intervention/exposure No outcome of interest Wrong study/publication type Wrong intervention/exposure Wrong or no comparator Wrong study/publication type No outcome of interest
No outcome of interest Wrong study/publication type Wrong or no comparator Study duration too short Wrong study population
No outcome of interest

STUDY

REASON FOR EXCLUSION

159 Annex 10. Excluded studies

STUDY

REASON FOR EXCLUSION

De Ruyter 2013 (408)
De SagrarioLopez-Meza 2018 (409) Den Biggelaar 2020 (410) Deschamps 1971 (411)
Ebbeling 2006 (258)
Ebbeling 2012 (257)
Fantino 2018 (412)
Farr 2021 (413)

Forster 1993 (414)
Franchi 2021 (415)
Frey 1976 (255)
Friedhoff 1971 (416)
Fritschka 2019 (417) Fuentealba Arevalo 2019 (418) Gehring 1990 (419)

Gerber 2020a
Gibson 2016 (420)
Ginieis 2018 (421)
Gligore 1971 (422)
Goto 1990 (423)
Griffioen-Roose 2013 (424)
Grotz 2017 (425)
Gui 2017 (426)
He 2018 (427)
Heckenmueller 2021 (428)
Hennon 1965 (429)
Hong 2018 (430)
Hu 2014 (431) IRCT20140310016925N3 2018 (432) Ismail 1984 (433)
Jensen 1982 (434)
Johnson 2007 (435)
Kant 2003 (436)
Kato 2020b
Kenney 2017 (437)
Kim 2019 (438)
Koebnick 2018 (439)
Kruesi 1987 (440)
Laforest-Lapointe 2021 (441) Larsson 2014 (442)
Larsson 2016 (443)
Lemeshow 2018 (444)
Lertrit 2017 (445)

Duplicate
NSS too high
Wrong study population Study duration too short Wrong intervention/exposure Wrong intervention/exposure Duplicate
Study duration too short

Wrong study/publication type No outcome of interest
NSS too high
Wrong study population Wrong study/publication type No outcome of interest Wrong study/publication type Full text not found

Wrong intervention/exposure Study duration too short
Full text not found
Wrong intervention/exposure Study duration too short

NSS too high
Wrong intervention/exposure Wrong intervention/exposure Wrong study/publication type Full text not found
Wrong intervention/exposure No outcome of interest
No outcome of interest Wrong intervention/exposure Wrong study/publication type Wrong intervention/exposure Wrong intervention/exposure Wrong intervention/exposure Wrong intervention/exposure Wrong intervention/exposure Wrong intervention/exposure Study duration too short Duplicate
Wrong intervention/exposure Wrong intervention/exposure No outcome of interest Duplicate

160 Health effects of the use of non-sugar sweeteners

STUDY

REASON FOR EXCLUSION

Lertrit 2018 (446)
Leung 2018 (447)
Lindseth 2014 (448) Lodefalk 2006 (449)
Lotto 2020 (450)
Lutsey 2008 (451)
Lutsey 2009 (452)
Maillot 2019 (453)
Maki 2008 (454)
Maloney 2019 (455)
Markus 2020 (456)
Marshall 2017 (457) Marshall 2018 (458) Marshall 2019 (459) Marshall 2019 (460) Marshall 2020 (461) Mayasari 2018 (462) McNaughton 2008 (463) Meyer-Gerspach 2018 (464) Miguel-Berges 2020 (465) Miranda Lora 2020 (466) Mirghani 2020c

Mirghani 2021 (467) Morin 2018 (468)
Mullie 2017 (469)
Nazari 2018 (470) NCT00381160 2006 (471) NCT04230824 2020 (472) NCT04857554 2021 (473) Nejadsadeghi 2018 (474) Nicklas 2003 (475) Nissensohn 2015 (476) Patel 2018 (477)

Petersen 2015 (478)
Porikos 1977 (479)
Porikos 1982 (480)
Qiu 2020 (481) Rusmevichientong 2018 (482) Samman 2020 (483) Sanchez-Delgado 2019 (47) Shaywitz 1994 (484)

Shin 2018 (485)
Small 2020
Soparkar 1978 (486) Stamataki 2020c (487)

Duplicate
Wrong intervention/exposure Wrong study/publication type Wrong study population Wrong intervention/exposure No outcome of interest
No outcome of interest Wrong intervention/exposure NSS too high
Study duration too short Study duration too short Wrong intervention/exposure Wrong intervention/exposure Wrong intervention/exposure Wrong intervention/exposure Wrong intervention/exposure Wrong or no comparator Wrong intervention/exposure Study duration too short
No outcome of interest
Study duration too short
No outcome of interest Duplicate
Wrong intervention/exposure Wrong study/publication type Wrong intervention/exposure Wrong intervention/exposure Wrong or no comparator Study duration too short Wrong intervention/exposure Wrong intervention/exposure Wrong intervention/exposure Wrong intervention/exposure No outcome of interest
Study duration too short Wrong or no comparator
No outcome of interest
No outcome of interest Wrong intervention/exposure Duplicate
Wrong study population Wrong intervention/exposure Duplicate (abstract)
No outcome of interest
Study duration too short

161 Annex 10. Excluded studies

STUDY

REASON FOR EXCLUSION

Stookey 2007 (488)
Storey 2009 (489) Sushanthi 2020 (490) Sylvetsky 2020 (491) Sylvetsky 2020b (492)
Tey 2017 (493)
Thomson 2019 (494)
Tucker 2006 (495) Turner-McGrievy 2016 (496) van den Eeden 1991 (497) Walker 1982 (498)

Walton 1993 (499) Wang 2017 (500) Williams 2017 (501) Wilson 2000 (502) Yao 2014 (503) Young 2018 (504) Zanela 2002 (505) Zhang 2021 (506) Zollner 1971 (507)

Wrong intervention/exposure No outcome of interest
Study duration too short Wrong study population Wrong or no comparator Study duration too short

NSS too high
No outcome of interest
No outcome of interest
No outcome of interest Wrong study/publication type Wrong study population Wrong study population Wrong intervention/exposure Study duration too short
No outcome of interest
No outcome of interest Wrong intervention/exposure Wrong intervention/exposure Wrong study population

a http://dx.doi.org/10.1016/j.clnesp.2020.09.651
b https://jglobal.jst.go.jp/en/detail?JGLOBAL_ID=202002239574388156 c https://amj.net.au/index.php/AMJ/article/viewFile/3712/1809

162 Health effects of the use of non-sugar sweeteners

ANNEX 11.

Differences in study selection between original review and current update

Table A11.1 Eligibility criteria in original review and update

Population

Intervention/exposure

Comparators

Outcomes

Study design

Duration

ADI: acceptable daily intake; NSS: non-sugar sweeteners.

Also included pregnant women

Also included NSS unspecified by name

Also included comparison of no/low vs high intakes of NSS

Also included mortality and pregnancy-related outcomes

Unchanged

Minimum of 13 days for
blood lipid outcomes,
1 year for disease incidence outcomes (i.e. incident cancer, cardiovascular disease, type 2 diabetes) and 7 days for all other outcomes

CHARACTERISTIC

ORIGINAL ELIGIBILITY CRITERIA

NEW CRITERIA

Included general, healthy population of adults (≥18 years) or children (<18 years)

Excluded diseased populations, in vitro studies and animal studies

Included any type of NSS, either as an individual intervention or in combination with other NSS

Excluded studies that did not specify the type of sweetener

Excluded studies where dose was above ADI

Any alternative intervention – for example, any other type of caloric or non-caloric sweetener, any type of sugar, no intervention, placebo, or plain water

Body weight, oral health, incidence of diabetes, eating behaviour, 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

Included parallel grouped or crossover (quasi-) randomized controlled trials, cluster randomized trials, nonrandomized controlled trials, prospective and retrospective cohort studies, case–control studies and cross- sectional studies

Minimum of 7 days

163 Annex 11. Differences in study selection between original review and current update

Table A11.2 Studies excluded from original because sweetener not specified, but included in update

Akdaş 1990 Andreatta 2008 Asal 1988
Azad 2016 Berkey 2004 Bleich 2014 Blum 2005 Bomback 2010 Bravo 1987a Campos 2015 Chan 2009 Chen 1991

Chia 2016 Connolly 1978
de Koning 2011 de Koning 2012 Drewnowski 2016 Duffey 2012 Ewertz 1990 Fagherazzi 2017 Forshee 2003 Fowler 2015 Geraldo 2013 Giammattei 2003 Hoover 1980

Howe 1980
Hunt 2015 InterActConsortium 2013 Kantor 1985
Kessler 1976
Kobeissi 2013
Kral 2008
Laverty 2015
Lin 2011
Ma 2016
Mahfouz 2014
Markey 2016
Morgan 1974
Morrison 1979
Morrison 1980
Morrison 1982 Mozaffarian 2011 Nettleton 2009
Norell 1986
O’Connor 2006
Ohno 1985
Pan 2013
Pergrin Marriott 2016 Peters 2016
Petherick 2014

Pfeiffer 2015 Piernas 2011 Piernas 2013 Radosavljević 2001 Risch 1988

Sakurai 2014 Saldana 2007 Schernhammer 2012 Schulze 2004 Silverman 1983 Souza 2016 Stellman 1986 Stellman 1988 Stepien 2016 Striegel-Moore 2006 Sullivan 1982

Tate 2012
Vanselow 2009 Vázquez-Durán 2016 Vyas 2015 Winkelmayer 2005 Wynder 1980 Yarmolinsky 2016 Zou 1990

164 Health effects of the use of non-sugar sweeteners

Table A11.3 Studies excluded from original review but included in update

STUDY

REASON FOR EXCLUSION FROM ORIGINAL REVIEW

REASON FOR INCLUSION IN UPDATE/ EXPANSION

No direct/concurrent comparison arm

Appleton 2001

Bhupathiraju 2013

Bouchard 2010

Bravo 1987

Crichton 2015

DeCastro 1993

Drewnowski 2013 Durán Agüero 2015 Englund-Ögge 2012 Fagherazzi 2013

Fowler 2008

Fung 2009 Halldorsson 2010 Kline 1978 Ledoux 2011 Ludwig 2001 Mackenzie 2006 Mahar 2007

Masic 2017

Maslova 2013 Paganini-Hill 2007

Peters 2014

Shoham 2008

Sylvetsky 2012

Taljaard 2013 Vázquez-Durán 2013 Winther 2016

Wrong study type

Wrong intervention

Wrong study type

Wrong study population

Wrong study type

Outcome irrelevant

Study duration too short

Wrong study type

Sweetener not defined

Comparison of habitual heavy users and non- users of ASB

Comparison of intakes of ASB Cross-sectional study an eligible study type

Case–control study an eligible study type

Comparison of intakes of diet soft drinks

Comparison of intakes of diet sodas

Cross-sectional study an eligible study type Comparison of intakes of stevia
Pregnant women eligible
Comparison of intakes of ASB

Comparison of intakes of ASB

Pregnant women eligible

Miscarriage eligible outcome for pregnant women

Cross-sectional study an eligible study type

Comparison of intakes of diet soda

Cross-sectional study an eligible study type

Sweetness liking an eligible outcome

Protocol of trial. Outcomes were weight, body composition, appetite and cognition

Intake of ASB during pregnancy and asthma and allergic rhinitis during childhood

Outcome was mortality

Study duration of 12 weeks

Cross-sectional study an eligible study type

Randomized controlled trial

Eligible study type, population, comparison and outcome

Sweetener defined in full text (Winther 2017)

No direct/concurrent comparison arm

Outcome irrelevant

No direct/concurrent comparison arm

Wrong outcome (no health outcome)

Wrong study population

Missing

ASB: artificially sweetened beverage

165 Annex 11. Differences in study selection between original review and current update

Table A11.4

Studies included in original review but excluded from update

STUDY

REASON FOR EXCLUSION FROM NEW REVIEW

Frey 1976

Lindseth 2014

Maki 2008

Porikos 1982

van den Eeden 1991

NSS level above ADI

Study design not eligible: before and after study (no parallel control arm)

NSS level above ADI

Study design not eligible: before and after study (no parallel control arm)

No outcome of interest (sleep)

Impossible to isolate the effect of NSS (comparison of 1) mentholated deionized water, 2) chlorhexidine gluconate with sodium fluoride,
3) chlorhexidine digluconate, and 4) stevioside with sodium fluoride)

Zanela 2002
ADI: acceptable daily intake; NSS: non-sugar sweeteners.

Table A11.5 Outcome data included in update but not in original review

STUDY

OUTCOME

ORIGINAL REVIEW

UPDATE/EXPANSION

Weight gain

Not reported in publication

Body weight

Standard error or standard deviation not reported

Body weight

Standard error or standard deviation not reported

Body weight

Not reported in publication

Body weight

Not reported in publication

Bes-Rastrollo 2006 Blackburn 1997 Kanders 1988
Reid 2007

Reid 2010

Obtained necessary data from other review

Imputed standard error

Obtained necessary data from authors

166 Health effects of the use of non-sugar sweeteners

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