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Health outcomes of non-nutritive sweeteners: analysis of the research landscape

Nutrition Journal201716:55

https://doi.org/10.1186/s12937-017-0278-x

Received: 19 January 2017

Accepted: 4 September 2017

Published: 8 September 2017

Abstract

Background

Food products containing non-nutritive sweeteners (NNSs) instead of sugar have become increasingly popular in the last decades. Their appeal is obviously related to their calorie-free sweet taste. However, with the dramatic increase in their consumption, it is reasonable and timely to evaluate their potential health benefits and, more importantly, potential adverse effects. The main aim of this scoping review was to map the evidence about health outcomes possibly associated with regular NNS consumption by examining the extent, range, and nature of research activity in this area.

Methods

We systematically searched Ovid MEDLINE, EMBASE and the Cochrane CENTRAL databases for studies on NNSs (artificial sweeteners or natural, non-caloric sweeteners, either used individually or in combination) using text terms with appropriate truncation and relevant indexing terms. All human studies investigating any health outcomes of a NNS intervention or exposure were eligible for inclusion. No studies were excluded based on language, study design or methodological quality. Data for each health outcome were summarized in tabular form and were discussed narratively.

Results

Finally, we included 372 studies in our scoping review, comprising 15 systematic reviews, 155 randomized controlled trials (RCTs), 23 non-randomized controlled trials, 57 cohort studies, 52 case-control studies, 28 cross sectional studies and 42 case series/case reports.

In healthy subjects, appetite and short term food intake, risk of cancer, risk of diabetes, risk of dental caries, weight gain and risk of obesity are the most investigated health outcomes. Overall there is no conclusive evidence for beneficial and harmful effects on those outcomes. Numerous health outcomes including headaches, depression, behavioral and cognitive effects, neurological effects, risk of preterm delivery, cardiovascular effects or risk of chronic kidney disease were investigated in fewer studies and further research is needed. In subjects with diabetes and hypertension, the evidence regarding health outcomes of NNS use is also inconsistent.

Conclusions

This scoping review identifies the needs for future research to address the numerous evidence gaps related to health effects of NNSs use.It also specifies the research questions and areas where a systematic review with meta-analyses is required for the proper evaluation of health outcomes associated to regular NNSs consumption.

Keywords

Non-nutritive sweetener Artificial sweetener Aspartame Saccharin Stevia Diabetes Cancer Dental caries Weight gain Overweight Obesity Scoping review

Introduction

In the last decades, growing concerns about health and quality of life have encouraged people to avoid the consumption of food rich in sugar, salt or fat [1, 2]. With increased consumer interest in reducing sugar intake, food products containing calorie-free alternatives (non-nutritive sweeteners; NNSs) have become increasingly popular [3, 4]. NNSs are generallyseveral hundred to several thousand times sweeter than sucrose [5]. Most of them do not contain any calories while some NNSs (e.g. aspartame) contain very few [6]. Each sweetener has specific characteristics of sweetness intensity, persistence of the sweet taste, coating of the teeth and aftertaste effect [7, 8].

Most of the NNSs approved for human consumption are synthetic (artificial sweeteners; AS). However, more and more NNSs of natural origin are available on the market (natural, non-caloric sweeteners; NNCSs). The most familiar NNCSs are Stevia rebaudiana-based products. Steviol glycosides, extracted from the plant Stevia include stevioside and rebaudioside A, but also other, less common glycosides [9].

With regard to the range of approved ASs there are differences among countries. In the United States for example, there are currently six ASs which the Food and Drug Administration (FDA) has approved for consumption (Table 1; [10] acesulfame-K, aspartame, neotame, saccharin, sucralose and advantame). In the European Union meanwhile, the range of currently approved ASs is wider, also including, for example, cyclamate [11, 12]. Stevia has been used as a sweetener for decades in some countries (e.g. Japan), while it was approved as a food additive just recently by the European Food Safety Authority (EFSA) [13] and the US FDA.
Table 1

Non-nutritive sweeteners available in the USA and the European Union, and their Acceptable Daily Intake levels, as defined by regulatory bodies

 

Acceptable Daily Intake defined by the FDA (mg/kg bw)

Acceptable Daily Intake defined by the SCF/EFSA (mg/kg bw)

ACE K

15

9

Advantame

32.8

5

Aspartame

50

40

Cyclamate

not approved

7

Luo Han Guo fruit extracts

not specified

not specified

Neohesperidine DC

not approved

5

Neotame

0.3

2

Saccharin

15

5

Sucralose

5

15

Steviol glycosides

4

4

Thaumatin

not approved

not specified

Abbreviations: EFSA European Food Safety Authority, FDA Food and Drug Administration, SCF Scientific Committee on Food (European Commission)

Parallel to the dramatic increase in the consumption of food and beverages sweetened with NNSs, concerns have been raised about their potential adverse health effects [1416]. Several studies investigated short-term consequences (e.g. on food intake, mood, blood pressure); others evaluated long-term health effects (e.g. on body weight, incidence of obesity, risk of cancer, risk of diabetes or dental caries) of NNSs. Overall, plenty of scientific studies have been published, postulating a wide variety of beneficial, but also negative health effects of NNSs.

Since scoping reviews are used to present a broad overview of the evidence pertaining to a topic irrespective of study quality, they can be seen as a hypothesis-generating exercise and are therefore the optimal method for examining this emerging area as a first approach [17]. The aim of this scoping review was to map the available evidence about the health outcomes possibly associated with regular NNS consumption by examining the extent, range, and nature of research activity in this area.

Objectives

Primary objectives of this scoping review were to:
  • Identify all potential health outcomes associated with regular NNS consumption;

  • Define the number and types of primary studies (i.e. studies that collect original data from subjects) available for each health outcome;

  • Identify any gaps in the evidence base for the health outcomes of regular NNS consumption.

Secondary objective of this scoping review was to:
  • Summarize available systematic reviews on the association of NNS consumption and health outcomes, compare their inclusion criteria and limitations, and determine whether a new systematic review in this area is justified.

Methods

We used the approach of a scoping review (including a process known as evidence mapping) [18, 19] to compile all relevant evidence about the health effects of NNS consumption from the scientific literature. This approach is based on a systematic literature search and the transparent assessment of the retrieved evidence for its relevance for the research question by presenting an overview of a potentially large and diverse body of literature pertaining to this broad research topic, without making restrictions based on study design and methodology. Furthermore, it seeks to provide a descriptive summary of the evidence without detailed critical appraisal of included individual studies.

Inclusion criteria

To be included, a primary study needed to meet all of the following criteria: a) a study on human beings (of any age, gender or health status); b) an intervention with or exposure to any type and any dosage of ASs (aspartame, acesulfame potassium, saccharin, sucralose, advantame, neotame, cyclamate, alitame, neohesperidin dihydrochalcone (DC)) or NNCSs (stevioside, rebaudioside A, thaumatin, brazzein) or NNSs (defined as any combination of AS and NNCS); c) a study reporting health effects of any type (both health outcomes and intermediate markers of health outcomes were included); d) no restriction on study design or language.

We also included relevant systematic reviews on the association of an NNS intervention/exposure and one or more defined health outcomes (every review describing or indicating a systematic search was regarded to be a systematic review).

In this manuscript we report on relevant systematic reviews, clinical trials, cohort studies, case-control and cross-sectional studies.

Search strategy

Ovid MEDLINE (ovidsp.ovid.com), EMBASE (www.embase.com) and the Cochrane CENTRAL database (www.cochranelibrary.com) were searched from inception to October Week 2 2015 for studies on AS and to January Week 3 2016 for studies on NNCS and NNS, using text words with appropriate truncation and relevant indexing terms (MeSH). The search was in the form [terms for artificial sweeteners/ natural, non-caloric sweeteners/non-nutritive sweeteners] and [human studies]. Electronic searches were limited neither in time nor in language. Electronic searches were followed by hand searching of reference lists of relevant review articles and included primary studies. Electronic searches were updated in May Week 4 2017.

Data extraction and management

Titles and abstracts were screened for inclusion by a single reviewer (SL). Only clearly irrelevant records were excluded at this stage. All potentially relevant abstracts and full papers were screened for inclusion by two reviewers independently using an inclusion/exclusion form specifically developed for the purpose of this scoping review (SL and IT). In case of disagreement, the subject was discussed among the two reviewers until a mutual decision could be made. When this was not possible, a third reviewer (JM) was consulted. A data extraction sheet was designed and piloted. Then two reviewers (SL and IT) independently extracted the following data for each included primary study: 1) first author; 2) year of publication; 3) study location; 4) study design; 5) aim of the study; 6) main characteristics and size of the study sample; 7) main characteristics of intervention/exposure and control; 8) outcome measures with direction of effect.

Intervention studies were classified as RCTs (with either parallel, or cross-over design) or non-randomized controlled trials (non-RCTs), while observational studies were classified as prospective or retrospective cohort studies, cross-sectional studies, case-control studies, ecological studies or case reports/case series. Data sheets were compared and in case of differences in the extracted data, the relevant information was checked again in the study article and corrected.

Data for each health outcome were summarized in tabular form and were discussed narratively. Bubble charts were used to highlight the main relationship among the types of NNS used in the studies as intervention/exposure, the health effects and the study types. Bubble charts are multi-variable graphs, whose plot points along a grid where the X and Y axis are separate variables (in our case they represent the type of sweetener and health outcomes).Additionally, the different colours of the plotted points represent a third variable (in our case they show the study type).

For each included systematic review following data were extracted: 1) first author; 2) year of publication; 3) date of search; 4) databases searched 5) aim of the review; 6) study design of eligible studies; 7) main characteristics of eligible intervention/exposure; 8) outcome(s) eligible for inclusion.

Results

The flow diagram of the literature search (PRISMA Flow Diagram adapted for the scoping review process) is shown in Fig. 1. For ASs a total of 7970 articles were identified in the initial literature search, of which 669 appeared to be potentially relevant. Fifteen papers could not be retrieved; all others were available for detailed full-text assessment. Finally, 317 articles fulfilled the inclusion criteria. This search focused on studies with ASs as the intervention or exposure; however, 11 primary studies with NNSs, 28 studies with diet beverages/diet sodas and one study with a combination of NNSs and sugar-alcohols were already identified at this stage. For NNCSs and NNSs, 3087 articles were identified in the original literature search, 112 full texts were screened for eligibility and finally 55 were included in the review. In 2017, after the update search of databases, 48 further studies were eligible for inclusion.
Fig. 1

Flow diagram for the systematic search on artificial sweeteners, natural non-caloric sweeteners and non-nutritive sweeteners. *All manuscripts which described neither a primary study nor were systematic reviews (e.g. narrative summaries, commentaries, and letters) were excluded as “Wrong publication format”

In total, 24 systematic reviews (Table 2), 175 randomized controlled trials (RCTs), 29 non-randomized controlled clinical trials (non-RCTs), 62 cohort studies, 52 case-control studies and 36 cross-sectional studies were included in this scoping review. We also found 42 case studies.
Table 2

Systematic reviews investigating health effects of non-nutritive sweeteners

First author, publication year

Population

Intervention/ Exposure

Outcome

Included study designs

Limitations

Date of search

Searched databases

Bernardo, 2016 [274]

adults and children

AS use

adverse clinical effects

comparative and epidemiological studies

ND

ND

MEDLINE; EMBASE; Cochrane Library; Lilacs/Scielo

Berry, 2016 [84]

ND

sucralose consumption

carcinogenic potential

ND

ND

ND

MEDLINE;

TOXFILE, BIOSIS Toxline; FOODLINE; CAB

Abstracts; Food Science and Technology Abstracts;

NTIS; EMBASE

Borkum, 2016 [275]

ND

migraine triggers (including aspartame)

oxidative stress in the brain

ND

published between1990–2014 and in English language

ND

MEDLINE

Brown, 2010 [22]

children (0–18 y)

AS consumption

metabolic health effects (food intake, weight change, diabetes, metabolic syndrome components)

ND

published in peer reviewed journals in English language; published full text available

ND

MEDLINE, Web of Science, EMBASE

Greenwood, 2014 [157]

generally healthy population

sugar- or artificially-sweetened beverage consumption

incident diabetes mellitus type 2 risk

prospective observational studies (min. Duration: 3 years)

published since 1990 and in English language

November 2009; updated: June 2013

Cochrane Library; MEDLINE; MEDLINE In-Process; EMBASE; CAB Abstracts; ISI Web of Science; BIOSIS

Cheungpasitporn, 2014 [135]

ND

sugar- or artificially-sweetened soda consumption

chronic kidney disease incidence

RCTs, case–control, cross-sectional or cohort studies

provided odds ratios, relative risks, hazard ratios or standardized incidence ratios with 95% confidence intervals

June 2014

MEDLINE, EMBASE, Cochrane Library, CENTRAL

Hendriksen, 2011 [276]

ND

added sugar and intense sweeteners

beneficial and hazardous health effects

ND

written in English or Dutch language

October 2008

ND

Imamura, 2016 [161]

adults without diabetes

artificially sweetened beverages

incidence of type 2 diabetes

prospective studies

no language or time limitations

May 2013;

updated: February 2014

MEDLINE; EMBASE;

Ovid; Web of Science

Miller, 2014 [181]

generally healthy population

low-calorie sweeteners from foods or beverages or as tabletop sweeteners

body weight or body composition

RCTs and prospective cohort studies

a minimum study duration of 2 weeks for RCTs and 6 months for prospective cohorts

September 2013

MEDLINE

Pereira, 2014 [180]

no limitation

ASB (or sugar- sweetened beverages) consumption

body weight or body fat

RCTs and prospective cohort studies

observational studies min. Duration of 6 months

March 2012

MEDLINE

Pereira, 2013 [277]

ND

DB/ASB consumption

body weight, obesity risk, type 2 diabetes, or cardiovascular disease

ND

studies in English language

September 2011

MEDLINE

Reid, 2016 [183]

pregnant women, infants, or children (<12 years of age)

early life NNS exposure (all types of NNS consumption)

long-term metabolic health (BMI, birth weight, growth

velocity, incidence of overweight/

obesity, change in adiposity, incidence of impaired

glucose tolerance, metabolic

syndrome, insulin resistance or type 2 diabetes)

RCTs and prospective cohort studies

min. Study duration of 6 months

July 2015

MEDLINE; EMBASE; Cochrane Library

Rogers, 2016 [182]

humans and animals

low-energy sweeteners consumption

energy intake, body weight, BMI

ND

no language or time limitations

February 2015

MEDLINE, EMBASE, Web of Science

Romo-Romo, 2016 [24]

adults

NNS consumption

glucose metabolism and appetite regulating hormones, development of metabolic chronic diseases

observational studies and clinical trials

follow up of at least 3 years in cohort studies

April 2015; updated: March 2016

MEDLINE, Cochrane Library, Trip Database

Russel, 2016 [278]

adult type 2 diabetes patients or obese subjects

nutrients (incl. Low-calorie sweeteners)

postprandial hyperglycemia

intervention trials

studies in English language

ND

MEDLINE, Web of Science

Shankar, 2013 [279]

ND

NNS consumption

obesity/weight gain; diabetes; cardiometabolic indicators

ND

ND

2012

MEDLINE

Spencer, 2016 [280]

humans and animals

aspartame, saccharin or sucralose consumption

fermentation, absorption, gastrointestinal symptoms

ND

full articles in English language

June 2015

MEDLINE, EMBASE

Timpe Behnen, 2013 [281]

diabetes patients

acesulfame, aspartame,luo han guo, monk fruit, neotame, rebiana, saccharin, stevia, and sucralose

diabetic control, including, but not limited to, blood glucose levels, postprandial blood glucose, HbA1c

clinical studies

studies in English language

May 2012

MEDLINE, Scopus

Wiebe, 2011 [23]

ND

a sweetener (e.g. non-caloric sweetener)

weight change, energy intake, lipids, HbA1C, insulin resistance

parallel or crossover RCT

follow-up at least 1 week in duration;

at least 10 participants per group,

no trials with placebo control

January 2011

MEDLINE, EMBASE, Cochrane Library CENTRAL, CAB Global

Oliver, 2015 [85]

ND

aspartame, ace-K, cyclamic acid and its salts, steviol glycosides, neohesperidin DC, neotame, saccharine and its salts, sucralose,aspartame-acesulfame salt, thaumatin

benefits and risks related to intense sweeteners

meta-analysis, RCTs, quasi experimental, cohort, case-control, cross-sectional studies

none

ND

MEDLINE, Cochrane Database of Systematic Reviews, Psychinfo

Onakpoya, 2015 [21]

adult volunteers (>18 y)

steviol glycoside

cardiovascular risk factors (blood pressure, blood sugar, cholesterol)

double-blind RCTs

No age, language or time restrictions. Studies in which steviol glycosides were combined with other dietary supplements were excluded

May 2014

MEDLINE, EMBASE, Amed, Cinahl, The Cochrane Library, Google Scholar

Poolsup, 2012 [282]

patients with hypertension

stevioside

systolic and diastolic blood pressure control

RCTs

published in English language

February 2012

MEDLINE, Science Direct, Cochrane Library, Wiley Online Library

Ulbricht, 2010 [20]

both adults and children

stevia

adverse effects, (pharmacology, kynetics, dosing, interactions, toxicology)

no restriction (both in vivo and in vitro studies)

no language restrictions

ND

AMED, CANCERLIT, CINAHL, CISCOM, Cochrane Library, EMBASE, HerbMed, International Pharmaceutical Abstracts, MEDLINE, NAPRALELT

Urban, 2015 [283]

ND

steviol glycosides and/or stevia leaf extracts of known concentrations

allergic reactions

no restriction (also animal and in vitro studies)

ND

October 2014

MEDLINE, Science Direct, Google Scholar

Wang, 2016 [284]

adults, pregnant women and infants (>6 mo)

FDA-approved sweeteners

energy sensing by the brain; gut hormones that may influence energy homeostasis; satiety and preference f r taste; eating behavior; body weight and composition

RCTs, non-RCT, not controlled trials, prospective cohorts

English language; cancer patients were excluded

ND

MEDLINE

Abbreviations: ASB artificially sweetened beverage, DB diet beverage, HbA1c glycosylated haemoglobin type A1C, ND not described, RCT randomized controlled trial; y, years; mo, months

Health outcomes assessed in the included studies

Health outcomes by intervention as investigated in primary studies are shown in Fig. 2. We first report short-term outcomes (appetite and short-term food intake), then long-term health outcomes in healthy populations (in alphabetical order: cancer, chronic kidney disease, dental caries, diabetes, headaches, neurocognitive outcomes, obstetric outcomes, weight gain and obesity). Finally, health outcomes in non-healthy populations are described.
Fig. 2

Health outcomes by intervention investigated in primary studies. a studies, where authors investigated effects of “artificial sweeteners” (no further details for the intervention/exposure is provided); b authors investigated the combined effects of two or more artificial sweeteners (type of sweeteners is described); c any type of “diet beverage”, where the type of sweetener is not defined; d combined effect of AS and NNCS was investigated or the intervention/exposure was described as “non-nutritive sweeteners” (without further details); e the investigated intervention/exposure is a combination of NNS and other non-sugar sweeteners (e.g. sugar alcohols). * haematological parameters, blood chemistries and hormone levels; **any other health outcome, which couldn’t be classified to any of the above listed categories (e.g. male fertility [289], offspring forearm fractures [290], emotional state [291], analgesia [292] or mortality [293]). Abbreviations: AS, artificial sweeteners; CVD, cardiovascular disease; NNS, non-nutritive sweeteners

Short-term outcomes

Appetite and short term food intake

Eating behavior and metabolic effects due to the exposure to NNSs were investigated in five systematic reviews among other outcomes [2024]. One review reported evidence for an appetite lowering effect of aspartame, whereas the other reviews reported conflicting evidence for the effects of Stevia and ASs in general on eating behavior.

The primary studies on short-term food intake focused on whether exposure to NNSs enhances the desire for sweet foods and drinks, leading to an increased food intake. From the included 60 primary studies, 32 were small, cross-over RCTs [2556] with a similar design: the subjects first consumed a “preload”, a food or drink sweetened with either NNSs or with sugar (a nutritive sweetener) or a food or drink which did not contain any sweetener (e.g. water). After a time delay subjects were offered an ad libitum meal and total energy intake was measured.

No effects of NNSs on short-term food intake or subjective awareness of hunger were described in 39 studies (9 parallel RCTs [53, 5764], 22 cross-over RCTs [2529, 31, 3339, 41, 43, 46, 50, 51, 5356], 7 non-RCTs [45, 6570] and 1 case-control study [71]); 10 studies described an increased [32, 40, 45, 47, 49, 52, 7275], while 11 studies described a decreased food intake or appetite [30, 42, 48, 7683] in the NNSs intervention group as compared to the sugar-receiving or placebo group.

Long-term health outcomes in healthy populations

Cancer

Berry et al. [84] systematically summarized studies on the carcinogenic potential of sucralose and concluded that sucralose does not demonstrate carcinogenic activity even when exposure levels are several orders of magnitude greater than the range of anticipated daily ingestion levels. Another, broadly focused systematic review published in 2015 [85] assessed cancer risk among several other health outcomes. Authors of this review also searched for diet beverage studies, but only narratively summarized their results and concluded that, based on the available data, it was not possible to establish a link between cancer risk and the consumption of ASs.

In total, we identified 51 primary studies assessing the association of NNS consumption and cancer risk. The investigated exposure was use of any type of ASs or use of a subtype of ASs (saccharin or aspartame) in 47 studies, while 4 studies investigated exposure to NNCSs. Cancer outcomes by type of exposure as investigated in primary studies are shown in Fig. 3.
Fig. 3

Cancer outcomes by exposure investigated in primary studies

Out of the identified 41 case-control studies reporting on the effect of NNSs on cancer, 32 assessed the relationship between NNS consumption and the risk of developing bladder cancer or urinary tract cancer. The results of these studies are controversial: 11 case-control studies describe a positive association between AS/NNS intake and bladder or urinary tract cancer risk [8696], while 20 report no association [97116].

Two case-control studies assessed the risk of brain cancer (no association with AS use [117, 118]), 1 study assessed the risk for colorectal cancer (significantly increased with AS use [119]), 2 studies investigated the risk of pancreatic cancer (no association with NNSs [120, 121]), 1 study investigated the risk of breast cancer (no association with AS use [122]) and 4 studies investigated the risk of any type or more types of cancer (no association with NNS use [123126]).

Three prospective cohort studies investigated the risk of lymphomas or other hematological malignancies [127, 128], 1 assessed the risk of biliary tract cancer [129], 1 assessed cancer incidence in general [130], 1 assessed the risk of tumor multiplicity in treated bladder cancer patients [131], 1 investigated the 5-year survival rate in urinary bladder cancer patients [132], while 2 retrospective cohort studies assessed the risk of bladder cancer [112, 133] (no significant associations were described in either of them).

The cross-sectional study described that breast cancer survivors compared to age-matched controls had significantly lower intakes of NNSs [134].

Chronic kidney disease

In a systematic review by Cheungpasitporn et al. [135], the 4 included studies assessed the association between consumption of artificially sweetened soda and chronic kidney disease. The authors concluded that consuming artificially sweetened soda did not increase the risk of chronic kidney disease in high-risk patients.

The primary studies we found on the association of NNS consumption and the risk of developing chronic kidney disease were 3 prospective cohort studies (describing no association [136138]), 1 case-control study (describing a significant positive association [139]) and 2 cross-sectional studies (one of them indicating a positive association [136, 140]).

Dental health (caries)

We found 16 intervention studies (14 RCTs [141154] and 2 non-RCTs [155, 156]) on the association of an NNS intervention and dental health. Details of these studies are summarized in Table 3.
Table 3

Characteristics of studies investigating the effects of non-nutritive sweeteners on dental outcomes

First author, publication year

Study sample (n)

Intervention/Exposure

Control

Outcome

Effect

Interventional studies: randomized controlled trials with parallel-group design

Beiswanger, 1998 [141]

children (1818)

sugar-free chewing gum containing AS and non-AS

no intervention

development of caries/caries prevalence

decreased development of caries

Lopez de Bocanera, 1999 [142]

both adults and children (32)

a solution/drink with AS

sugared solution/drink

salivary or plaque pH

no effect on pH

Interventional studies: randomized controlled trials with cross-over design

Brambilla, 2014 [143]

adults (20)

a solution/drink with stevioside

sugared solution/drink

salivary or plaque pH

less acidogenic (increased) pH

Jawale, 2012 [144]

adults (20)

diet soft drink

sugared solution/drink

salivary or plaque pH

less acidogenic (increased) pH

Manning, 1993 [145]

adults (10)

sugar-free chewing gum containing AS and non-AS

sugared chewing gum

salivary or plaque pH

less acidogenic (increased) pH

Mendes de Santa, 2014 [146]

adults (9)

a solution/drink with a combination of NNS

sugared solution/drink

salivary or plaque pH

less acidogenic (increased) pH

Mentes, 2001 [147]

adults (29)

a solution/drink with AS and non-AS

sugared solution/drink

salivary or plaque pH

less acidogenic (increased) pH

Meyerowitz, 1996 [148]

age group not described (14)

a solution/drink with sucralose

sugared solution/drink

salivary or plaque pH

less acidogenic (increased) pH

Park, 1993 [149]

age group not described (5)

sugar-free chewing gum containing sucralose/ ace K

another NNS

salivary or plaque pH

no difference in pH

Park, 1995 [150]

adults (8)

sugar-free chewing gum containing AS or non-AS

sugared chewing gum; no intervention

salivary or plaque pH

less acidogenic (increased) pH

Roos, 2002 [151]

children (17)

diet soft drink

sugared solution/drink

salivary or plaque pH

less acidogenic (increased) pH

Steinberg, 1995 [152]

age group not described (10)

a solution/drink with sucralose

sugared solution/drink

salivary or plaque pH

less acidogenic (increased) pH

Steinberg, 1996 [153]

age group not described (12)

a solution/drink with sucralose

sugared solution/drink

salivary or plaque pH

less acidogenic (increased) pH

Zanela, 2002 [154]

children (T: 200)

a solution/drink with stevioside

chlorhexidine gluconate

amount of plaque formed

less effective in decreasing the amount of plaque formed

Interventional studies: non-randomized controlled trials

Mühlemann, 1985 [155]

adults (T:2)

a solution/drink with aspartame

sugared solution/drink

salivary or plaque pH

no effect on pH

Syrrakou, 1993 [156]

age group not described (15)

a solution/drink with sucralose

sugared solution/drink

salivary or plaque pH

less acidogenic (increased) pH

Observational studies: case-control studies

Grenby, 1975 [287]

adults (24)

saccharin instead of sucrose

sugared solution/drink

amount of plaque formed

decreased amount of plaque formed

Observational studies: cross-sectional studies

Serra-Majem, 1993 [288]

age group not described (893)

AS in regular diet

development of caries/caries prevalence

decreased development of caries

Abbreviations: AS artificial sweetener, ace K acesulfame potassium, n total number of participants, non-AS a non-sugar sweetener other than NNS (e.g. sugar alcohols)

Only two of the studies mentioned above described no differences between intervention and control groups [142, 155]; all other studies described a less acidogenic (increased) oral pH after the intervention as compared to the sugar-containing control.

Diabetes

In a systematic review published in 2014 [157], three included publications on 4 cohorts investigated the association between intake of artificially sweetened soft drinks and risk of type-2 diabetes [158160] using additional information provided by the authors of two of the publications [158, 159]. The review reported an increased risk of diabetes when consuming 330 ml/day of artificially sweetened soft drinks; however, substantial heterogeneity was described among the cohort studies. Also, another systematic review published in 2016 [161] described a positive association between the consumption of artificially sweetened beverages and type-2 diabetes incidence; however, the authors of this review rated their findings as biased.

We found 6 prospective cohort studies (4 with an AS exposure and 2 with a “diet beverage” exposure), 1 retrospective cohort study (with AS exposure) and 1 case-control study (with AS exposure) on the risk of developing diabetes. These studies are summarized in Table 4.
Table 4

Cohort studies on the association of AS consumption and risk of developing diabetes

First author, publication year

Study sample

Number of participants

Exposure

Main outcome

Direction of effect

Prospective cohort studies

Bhuphatiraju, 2013 [165]

female nurses (age 30–55 y)

+ male health professionals (age 40–75 y)

74,749 + 39,059

ASB

risk of type 2 diabetes

deKonig, 2011 [160]

middle-aged (40–75 y) male health care providers

40,389

ASB

incidence of type 2 diabetes

Fagherazzi, 2013 [162]

women

66,118

ASB

risk of type 2 diabetes

↑↑

Fagherazzi, 2017 [163]

women

61,440

AS in packets or tablets

risk of type 2 diabetes

↑↑

Palmer, 2008 [285]

women (age 21–69 y)

43,960

diet soft drink

risk of type 2 diabetes

Schulze, 2004 [217]

healthy women

91,249

diet soft drink

risk of diabetes

Sakurai, 2014 [286]

men

2037

diet soda

risk of type 2 diabetes

↑↑

Retrospective cohort studies

Armstrong, 1975 [166]

bladder cancer patients

+ patients with other cancers

18,733 + 19,709

saccharin

prevalence of diabetes

Case-control study

The Inter Act Consortium, 2013 [164]

type 2 diabetes cases

+ controls

11,684 + 15,374

artificially sweetened soft drink

incidence of type 2 diabetes

Abbreviations: ASB artificially sweetened beverage consumption, y years, AS artificial sweeteners; ↑ means that a positive association was suggested in the study, but this was not significant; ↑↑ means a significant positive association; − means that there was no (significant) difference in the outcome between the intervention and control group

Among the studies investigating the exposure to AS, 2 prospective cohort studies [162, 163] and one case-control study [164] described an increased risk of type-2 diabetes, while 2 prospective [160, 165] and 1 retrospective cohort studies [166] found no association between AS consumption and risk of diabetes. There were no studies investigating diabetes risk in association with NNCS consumption.

Headaches

We found 3 RCTs [167169] with a cross-over design and 2 cohort studies [170, 171] investigating the effect of AS on headaches. These included either healthy populations or populations with a subjectively reported sensitivity to AS or people with a history of migraines. Two of them (one RCT [168] and one cohort study [170]) described a significant positive association, in the others no significant association was found between AS consumption and headaches.

Cognitive effects, mental health

RCTs assessing the behavior and mood of essentially healthy children after they were given a preload of either an artificially sweetened or sugar-sweetened food or beverage found no consistent effect of ASs on behavior. Most of the interventional and observational studies investigating the effect of an AS preload on cognitive abilities in healthy children and adults demonstrated that there was no association between cognitive performance, measured by an array of tests, and the intake of ASs in different forms.

Three studies (2 RCTs and 1 cohort study) investigated the effect of AS on depression and described an increased risk of developing depression symptoms or increased severity of symptoms in mood disorder patients [172174]. In 1 case-control study, consumption of saccharin was significantly positively associated with the risk of Alzheimer’s disease [175].

Obstetric outcomes

Three cohort studies investigated the effect of AS consumption and preterm delivery [176178], two of them describing a significant positive, while one described no association. One case-control study described no association between saccharin use before conception or during pregnancy and spontaneous abortion [179].

Weight change

We found 4 systematic reviews addressing the question whether NNS consumption has an unfavorable or favorable effect on body weight [22, 180182]. Details of these reviews are described in Table 2. Miller et al. [181] indicated, based on data from RCTs, that substituting low-calorie sweeteners (LCS, including NNSs and sugar-alcohols) for calorically dense alternatives resulted in a modest reduction of body weight, body mass index (BMI), fat mass, and waist circumference. Rogers et al. [182] concluded, based on results of relevant RCTs, that low-energy sweetener consumption does not increase body weight. The meta-analysis of observational studies showed a significant positive association between LCS intake and slightly increased BMI, but no association with body weight or fat mass. Pereira et al. [180] concluded that results of the epidemiologic studies are highly inconsistent.

A systematic review [22] focusing on metabolic health effects of AS consumption in pediatric populations identified 3 large cohort studies with long-term follow-up, supporting the existence of an association between ASB (artificially sweetened beverage) consumption and weight gain in children, while 2 other prospective cohort studies described no or an inverse association with obesity. The identified 3 RCTs on children described no differences in weight or BMI between the NNS and the control groups.

Another systematic review [183] focusing on long-term metabolic effects of early NNS consumption concluded that the current evidence of the long-term metabolic effects of NNS exposure during gestation, infancy, and childhood is limited and inconsistent.

We found 31 interventional studies (27 RCTs [58, 61, 62, 74, 77, 184205] and 4 non-RCTs [67, 68, 79, 206]) and 36 observational studies [158, 159, 202, 203, 207241] on the effect of NNS consumption on BMI or weight change, including recently published studies, which were not included in the systematic reviews presented above.

Of the 27 RCTs, 14 reported a weight reduction after the intervention with NNSs or diet beverages, 2 reported an increase in weight, while in 11 RCTs no weight change was observed. After subdividing the RCTs according to the type of exposure, we found 15 RCTs with an AS intervention, 8 describing a decrease in body weight after the AS intervention as compared to the (sugar-containing or unmodified) control intervention, 1 describing an increase, while in 6 AS intervention studies no differences were observed between the two groups. There were 3 RCTs with a NNCS (stevia) intervention [187, 204, 242]. None of them described a difference in change of body weight between the intervention and control groups.

Of the 17 prospective cohort studies, 10 described a positive association (either statistically significant or a non-significant trend) between NNS or diet beverage consumption and weight gain/increased BMI [159, 207211, 216, 218, 237, 239], 3 observed an inverse association [214, 215, 217], while in 4 prospective cohort studies no association [212, 213, 219, 220] between body weight and NNS consumption was found. When investigating the subgroup of prospective cohort studies with a clear AS intervention (8 studies), we found 7 studies describing a positive [208210, 216, 218, 237, 239] and 1 study describing no association [219] between AS consumption and weight gain/increased BMI. There were no cohort studies with a NNCS intervention reporting on weight gain or obesity.

Of the 17 cross-sectional studies, 12 described a positive [158, 222226, 229233, 241], 2 a negative [227, 235] and 3 no association [221, 228, 234] between NNS or diet beverage consumption and weight gain/increased BMI.

Health outcomes in non-healthy populations (diabetes and hypertension)

There are two main disease groups with a relatively wide literature of NNS intervention studies. In type-1 and type-2 diabetes patients, the effects of NNS use on diabetic control, including, but not limited to, blood glucose levels, postprandial blood glucose, and glycated hemoglobin (HbA1c), are widely investigated. We found 21 interventional studies (13 RCTs [33, 198, 243253] and 4 non-RCTs [254257] with an AS intervention, and 4 RCTs [193, 258260]) and 2 non-RCT with an NNCS intervention [261] on this topic.Most of the studies described no difference in diabetic patients on diabetic control between the NNS intervention and the control group. Some studies investigated the glycemic effects of NNSs in people with insulin resistance and impaired glucose tolerance [204, 206, 262].

The other disease group consists of hypertensive patients, where the role of NNSs in blood pressure control has been investigated. We found 9 RCTs [187, 193, 242, 259, 263267], 4 prospective cohort studies [268271], 1 case-control study [272] and 1 cross-sectional study [273] on this question, with controversial results.

Discussion

Summary of findings

Overall the evidence for health outcomes of AS is inconsistent and there are numerous gaps in the evidence base. In healthy subjects, appetite and short term food intake, risk of cancer, risk of diabetes, risk of dental caries, weight gain and risk of obesity were the most investigated health outcomes.

In case of the health outcome appetite and short term food intake, a majority of studies were short interventions with a cross-over design. A smaller part were randomized controlled trials with an intervention duration of 4 weeks up to 18 months. In case of the longer interventions, the type and dosage of the NNS was often not defined.

Bladder cancer and cancer of the urinary tract were investigated in multiple studies. For this type of cancer a systematic review may provide conclusive evidence. Most of the studies on urinary tract cancer investigated effects of artificial sweeteners in general; a smaller number investigated the effects of aspartame or saccharin. Other types of cancer were investigated in only one or a low number of studies.

We also found several studies on the role of NNS in dental caries prevention. Included studies suggested that stevia in chewing gum or NNCS beverages instead of sugar-sweetened beverages may be an effective tool for dental caries prevention. However, it has to be mentioned, that while sugar alcohols are widely used in chewing gums for caries prevention, and the literature on their effects is broad, the effects of NNCS on dental caries is investigated in a limited number of studies. In addition, in these studies, NNCSs were often combined with sugar alcohols. It would be interesting to see more comparative studies on the effectiveness of NNCS alone versus other interventions in influencing dental plaque pH; or studies with a longer intervention period and follow-up.

The effect of NNS on risk of diabetes was investigated in a limited number of cohort studies. These studies mainly focused on artificially sweetened beverage or diet beverage consumption and described different directions of effect. Further studies, focusing on special types of NNS (also including NNCS), are required.

Intervention studies on weight change focused mainly on the question whether NNS can be efficiently used in weight management. As part of weight loss intervention programs, more intervention studies would be required, to investigate the effects of NNS alone on body weight in both overweight, obese and normal-weight subjects. This would be especially important, since it is very difficult in observational studies to evaluate causality between NNS consumption and BMI/weight change and therefore results of these studies have to be interpreted with caution. A positive association between NNS consumption and weight gain in observational studies may be the consequence of and not the reason for overweight and obesity. Moreover, other factors, such as population characteristics, may influence the results of observational studies.

In subjects with diabetes, the effects of NNS were investigated mainly on glycemic control. Because of the heterogeneous, if not contradictory results, a thorough analysis of these findings in a full-fledged systematic review including meta-analyses, subgroup and sensitivity analyses is needed and might help to resolve some of the ongoing uncertainties. Further studies on long-term patient-relevant outcomes in diabetes are required.

The effect of NNS on lowering blood pressure in hypertensive patients should also be analyzed in a high quality systematic review and meta-analysis.

Regarding NNCS, although Stevia is increasingly used as a sweetener, the number of studies on its health effects is limited as of now. Studies investigating the effects of NNCS on cancer or diabetes risk are completely lacking, while there are only few studies on weight gain and obesity risk. Clearly, there is a need for further research.

Eligible NNS not addressed by any of the included primary studies were: neotame, alitame, neohesperidin DC, thaumatin and brazzein.

Strength and limitations of this scoping review

The strength of our scoping review is its inclusion of all types of primary studies and systematic reviews which investigate any health effect of any NNS in any population. We are therefore able to present a comprehensive overview of the available scientific evidence on health effects of NNS.

Our scoping review might be limited by the following factors. Firstly, the literature search was conducted in three major and comprehensive databases, but we might have inadvertently missed relevant studies listed in other databases. Secondly, the title abstract screening was conducted by one reviewer who might have inadvertently excluded relevant studies at the first stage of the screening. This limitation might be evened out by conducting the literature search in two steps. In the second step, relevant references for both topics were identified and the chances for including all relevant references in our review were increased.

Detailed assessment of the study quality is not covered in a scoping review and was not conducted in the context of our scoping review. Therefore, information gathered on the health outcome includes only its direction of effect but no information on the internal or external validity of the study results.

Discussion of findings in light of other evidence summaries

In our scoping review we found a large number of studies of different designs, investigating effects of different types of NNS in different populations on a variety of health outcomes.

Systematic reviews to summarize the available evidence are already available (Table 2). However, they often have methodological limitations (e.g. language limitation of the search, electronic search in only one database, etc.) or a narrow scope.

There are systematic reviews, which also included key words for “diet soda” and “diet beverage” in their search strategy. There are several, primarily observational studies, where the exposure is defined as “diet”, which may indicate NNS-containing beverages, but further details are often not provided. Therefore, it is clearly a challenge when trying to synthesize the evidence to decide, how to deal with studies describing the intervention/exposure as “diet beverage”, “diet drink” or “diet soda” only. We also included such studies in this scoping review; however, it has to be mentioned that we did not include specific search terms for “diet” beverages/sodas in our search strategy, therefore the list of studies reporting on the effects of diet beverage etc. may be incomplete.

Implications of findings for practice, policy and future research

Current evidence demonstrates that there is a need for both further primary research and high quality comprehensive systematic reviews including meta-analyses, to inform future recommendations about the health benefits and risks of NNS to advise and support health care practice and public health decision-making.

This scoping review highlights the need for studies which investigate the long-term effects of individual sweeteners on some of the less well-researched health outcomes (e.g. headaches, depression or other mood disorders, Alzheimer’s disease, risk of preterm delivery). Future studies need to be rigorous in design and conduct, with well-defined interventions (providing information on type and dosage of the non-nutritive sweetener) and controls. Study reports should include detailed descriptions of all methodological aspects to enable proper interpretation of the results.

Systematic reviews are required for health outcomes with a large number of primary studies, but without conclusive evidence (e.g. appetite and short term food intake, risk of cancer, dental caries, risk of diabetes, glycaemic control in subjects with diabetes and blood pressure control in hypertensive patients) to support the formulation of recommendations and to be able to decide whether further, well-designed primary studies are required.

Conclusions

There are numerous gaps in evidence related to the health effects of NNS in both healthy and non-healthy populations. In healthy subjects appetite and short term food intake, risk of cancer, risk of diabetes, risk of dental caries are the most investigated health outcomes, all of them without any conclusive evidence. There is a need for well-conducted systematic reviews to quantitatively summarize results and assess their validity. Besides, there are numerous health outcomes, like incidence of headaches in association with NNS consumption, depression, Alzheimer’s disease, risk of preterm delivery, behavioural effects, cardiovascular effects or risk of chronic kidney disease, which were investigated in only few studies and further research activity is needed. A systematic review may also help to enable formulating recommendations for subjects with diabetes and hypertension on using NNS.

Abbreviations

AS: 

Artificial sweeteners

EFSA: 

European Food Safety Authority

FDA: 

Food and Drug Administration

LCS: 

Low-calorie sweeteners

MeSH: 

Medical Subject Headings

NNCS: 

Natural, non-caloric sweetener

NNS: 

Of non-nutritive sweetener

RCT: 

Randomized controlled trial

Declarations

Acknowledgements

We would like to thank Annika Wenzel for reviewing our manuscript for language accuracy.

Funding

This work was commissioned and financially supported by the World Health Organization (WHO). The article processing charge was funded by the German Research Foundation (DFG) and the University of Freiburg in the funding program Open Access Publishing.

Availability of data and materials

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

Authors’ contributions

SL and IT developed search strategy; acquired trial reports, selected trials for inclusion and extracted data; JM supervised the work; SL prepared the first review draft. All authors read, commented and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Cochrane Hungary, Medical Center, University of Pécs
(2)
Cochrane Germany, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
(3)
Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité – U1153, Inserm / Université Paris Descartes, Cochrane France, Hôpital Hôtel-Dieu

References

  1. Siervo M, Montagnese C, Mathers JC, Soroka KR, Stephan BC, Wells JC. Sugar consumption and global prevalence of obesity and hypertension: an ecological analysis. Public Health Nutr. 2014;17:587–96.PubMedView ArticleGoogle Scholar
  2. Stanhope KL. Sugar consumption, metabolic disease and obesity: the state of the controversy. Crit Rev Clin Lab Sci. 2016;53:52–67.PubMedView ArticleGoogle Scholar
  3. Martyn DM, Nugent AP, McNulty BA, O'Reilly E, Tlustos C, Walton J, Flynn A, Gibney MJ. Dietary intake of four artificial sweeteners by Irish pre-school children. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2016;33:592–602.PubMedGoogle Scholar
  4. Li XE, Lopetcharat K, Drake MA. Parents' And children's acceptance of skim chocolate milks sweetened by monk fruit and stevia leaf extracts. J Food Sci. 2015;80:S1083–92.PubMedView ArticleGoogle Scholar
  5. Fujimaru T, Park JH, Lim J. Sensory characteristics and relative sweetness of tagatose and other sweeteners. J Food Sci. 2012;77:S323–8.PubMedView ArticleGoogle Scholar
  6. Chattopadhyay S, Raychaudhuri U, Chakraborty R. Artificial sweeteners - a review. J Food Sci Technol. 2014;51:611–21.PubMedView ArticleGoogle Scholar
  7. Patil S, Ravi R, Saraswathi G, Prakash M. Development of low calorie snack food based on intense sweeteners. J Food Sci Technol. 2014;51:4096–101.PubMedView ArticleGoogle Scholar
  8. Nahon DF, Roozen JP, de Graaf C. Sensory evaluation of mixtures of maltitol or aspartame, sucrose and an orange aroma. Chem Senses. 1998;23:59–66.PubMedView ArticleGoogle Scholar
  9. Ceunen S, Geuns JM. Steviol glycosides: chemical diversity, metabolism, and function. J Nat Prod. 2013;76:1201–28.PubMedView ArticleGoogle Scholar
  10. US Food, Drug Administration. High-Intensity Sweeteners [http://www.fda.gov/food/ingredientspackaginglabeling/foodadditivesingredients/ucm397716.htm (last accessed 08 May 2017).]
  11. Roberts A. The safety and regulatory process for low calorie sweeteners in the United States. Physiol Behav. 2016;Google Scholar
  12. Mortensen A. Sweeteners permitted in the EuropeanUnion: safety aspects. Scand J Food Nutr. 2006;50:104–16.View ArticleGoogle Scholar
  13. Revised exposure assessment for steviol glycosides for the proposed uses as a food additive. [Available from: http://www.efsa.europa.eu/de/efsajournal/pub/1972].
  14. Choudhary AK, Lee YY. Neurophysiological symptoms and aspartame: what is the connection? Nutr Neurosci. 2017:1–11.Google Scholar
  15. Sylvetsky Meni AC, Swithers SE, Rother KI. Positive association between artificially sweetened beverage consumption and incidence of diabetes. Diabetologia. 2015;58:2455–6.PubMedPubMed CentralView ArticleGoogle Scholar
  16. Schernhammer ES, Bertrand KA, Birmann BM, Sampson L, Willett WC, Feskanich D. Consumption of artificial sweetener- and sugar-containing soda and risk of lymphoma and leukemia in men and women. Am J Clin Nutr. 2012;96:1419–28.PubMedPubMed CentralView ArticleGoogle Scholar
  17. Peters MD, Godfrey CM, Khalil H, McInerney P, Parker D, Soares CB. Guidance for conducting systematic scoping reviews. Int J Evid Based Healthc. 2015;13:141–6.PubMedView ArticleGoogle Scholar
  18. Schmucker C, Motschall E, Antes G, Meerpohl JJ. Methods of evidence mapping. A systematic review. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2013;56:1390–7.PubMedView ArticleGoogle Scholar
  19. Colquhoun HL, Levac D, O'Brien KK, Straus S, Tricco AC, Perrier L, Kastner M, Moher D. Scoping reviews: time for clarity in definition, methods, and reporting. J Clin Epidemiol. 2014;67:1291–4.PubMedView ArticleGoogle Scholar
  20. Ulbricht C, Isaac R, Milkin T, Poole EA, Rusie E, Grimes Serrano JM, Weissner W, Windsor RC, Woods J. An evidence-based systematic review of stevia by the natural standard research collaboration. Cardiovasc Hematol Agents Med Chem. 2010;8:113–27.PubMedView ArticleGoogle Scholar
  21. Onakpoya IJ, Heneghan CJ. Effect of the natural sweetener, steviol glycoside, on cardiovascular risk factors: a systematic review and meta-analysis of randomised clinical trials. Eur J Prev Card. 2015;22:1575–87.View ArticleGoogle Scholar
  22. Brown RJ, de Banate MA, Rother KI. Artificial sweeteners: a systematic review of metabolic effects in youth. Int J Pediatr Obes. 2010;5:305–12.PubMedPubMed CentralView ArticleGoogle Scholar
  23. Wiebe N, Padwal R, Field C, Marks S, Jacobs R, Tonelli M. A systematic review on the effect of sweeteners on glycemic response and clinically relevant outcomes. BMC Med. 2011;9Google Scholar
  24. Romo-Romo A, Aguilar-Salinas CA, Brito-Cordova GX, Diaz RAG, Valentin DV, Almeda-Valdes P. Effects of the non-nutritive sweeteners on glucose metabolism and appetite regulating hormones: systematic review of observational prospective studies and clinical trials. PLoS One. 2016;11Google Scholar
  25. Anderson GH, Saravis S, Schacher R, Zlotkin S, Leiter LA. Aspartame: effect on lunch-time food intake, appetite and hedonic response in children. Appetite. 1989;13:93–103.PubMedView ArticleGoogle Scholar
  26. Anton SD, Martin CK, Han H, Coulon S, Cefalu WT, Geiselman P, Williamson DA. Effects of stevia, aspartame, and sucrose on food intake, satiety, and postprandial glucose and insulin levels. Appetite. 2010;55:37–43.PubMedPubMed CentralView ArticleGoogle Scholar
  27. Bellissimo N, Pencharz PB, Thomas SG, Anderson GH. Effect of television viewing at mealtime on food intake after a glucose preload in boys. Ped Res. 2007;61:745–9.View ArticleGoogle Scholar
  28. Bellissimo N, Thomas SG, Goode RC, Anderson GH. Effect of short-duration physical activity and ventilation threshold on subjective appetite and short-term energy intake in boys. Appetite. 2007;49:644–51.PubMedView ArticleGoogle Scholar
  29. Beridot-Therond ME, Arts I, Fantino M, De La Gueronniere V. Short-term effects of the flavour of drinks on ingestive behaviours in man. Appetite. 1998;31:67–81.PubMedView ArticleGoogle Scholar
  30. Birch LL, McPhee L, Sullivan S. Children's Food intake following drinks sweetened with sucrose or aspartame: time course effects. Physiol Behav. 1989;45:387–95.PubMedView ArticleGoogle Scholar
  31. Black RM, Leiter LA, Anderson GH. Consuming aspartame with and without taste: differential effects on appetite and food intake of young adult males. Physiol Behav. 1993;53:459–66.PubMedView ArticleGoogle Scholar
  32. Branton A, Akhavan T, Gladanac B, Pollard D, Welch J, Rossiter M, Bellissimo N. Pre-meal video game playing and a glucose preload suppress food intake in normal weight boys. Appetite. 2014;83:256–62.PubMedView ArticleGoogle Scholar
  33. Bryant CE, Wasse LK, Astbury N, Nandra G, McLaughlin JT. Non-nutritive sweeteners: no class effect on the glycaemic or appetite responses to ingested glucose. Eur J Clin Nutr. 2014;68:629–31.PubMedPubMed CentralView ArticleGoogle Scholar
  34. Carvalho P, Sousa M, Barros R, Padrao P, Moreira P, Teixeira V. Impact of morning ingestion of sugary and sweetened beverages on energy and fluid intake throughout day. Ann Nutr Metab. 2013;63:1448–9.Google Scholar
  35. Cuomo R, Savarese MF, Sarnelli G, Nicolai E, Aragri A, Cirillo C, Vozzella L, Zito FP, Verlezza V, Efficie E, Buyckx M. The role of a pre-load beverage on gastric volume and food intake: comparison between non-caloric carbonated and non-carbonated beverage. Nutr J. 2011;10:114.PubMedPubMed CentralView ArticleGoogle Scholar
  36. DellaValle DM, Roe LS, Rolls BJ. Does the consumption of caloric and non-caloric beverages with a meal affect energy intake? Appetite. 2005;44:187–93.PubMedView ArticleGoogle Scholar
  37. Flood JE, Roe LS, Rolls BJ. The effect of increased beverage portion size on energy intake at a meal. J Am Diet Assoc. 2006;106:1984–90. discussion 90PubMedView ArticleGoogle Scholar
  38. Ford HE, Peters V, Martin NM, Sleeth ML, Ghatei MA, Frost GS, Bloom SR. Effects of oral ingestion of sucralose on gut hormone response and appetite in healthy normal-weight subjects. Eur J Clin Nutr. 2011;65:508–13.PubMedView ArticleGoogle Scholar
  39. Holt SH, Sandona N, Brand-Miller JC. The effects of sugar-free vs sugar-rich beverages on feelings of fullness and subsequent food intake. Int J Food Sci Nutr. 2000;51:59–71.PubMedView ArticleGoogle Scholar
  40. King NA, Appleton K, Rogers PJ, Blundell JE. Effects of sweetness and energy in drinks on food intake following exercise. Physiol Bahav. 1999;66:375–9.View ArticleGoogle Scholar
  41. Lavin JH, French SJ, Read NW. The effect of sucrose- and aspartame-sweetened drinks on energy intake, hunger and food choice of female, moderately restrained eaters. Int J Obes. 1997;21:37–42.View ArticleGoogle Scholar
  42. Maersk M, Belza A, Holst JJ, Fenger-Gron M, Pedersen SB, Astrup A, Richelsen B. Satiety scores and satiety hormone response after sucrose-sweetened soft drink compared with isocaloric semi-skimmed milk and with non-caloric soft drink: a controlled trial. Eur J Clin Nutr. 2012;66:523–9.PubMedView ArticleGoogle Scholar
  43. Melanson KJ, Westerterp-Plantenga MS, Campfield LA, Saris WHM. Blood glucose and meal patterns in time-blinded males, after aspartame, carbohydrate, and fat consumption, in relation to sweetness perception. Brit J Nutr. 1999;82:437–46.PubMedGoogle Scholar
  44. Monneuse MO, Bellisle F, Louis-Sylverstre J. Responses to an intense sweetener in humans: immediate preference and delayed effects on intake. Physiol Bahav. 1991;49:325–30.View ArticleGoogle Scholar
  45. Naismith DJ, Rhodes C. Adjustment in energy intake following the covert removal of sugar from the diet. J Human Nutr Diet. 1995;8:167–75.View ArticleGoogle Scholar
  46. Rodin J. Comparative effects of fructose, aspartame, glucose, and water preloads on calorie and macronutrient intake. Am J Clin Nutr. 1990;51:428–35.PubMedGoogle Scholar
  47. Rogers PJ, Carlyle JA, Hill AJ, Blundell JE. Uncoupling sweet taste and calories: comparison of the effects of glucose and three intense sweeteners on hunger and food intake. Physiol Bahav. 1988;43:547–52.View ArticleGoogle Scholar
  48. Rogers PJ, Burley VJ, Alikhanizadeh LA, Blundell JE. Postingestive inhibition of food intake by aspartame: importance of interval between aspartame administration and subsequent eating. Physiol Behav. 1995;57:489–93.PubMedView ArticleGoogle Scholar
  49. Rogers PJ, Blundell JE. Separating the actions of sweetness and calories: effects of saccharin and carbohydrates on hunger and food intake in human subjects. Physiol Behav. 1989;45:1093–9.PubMedView ArticleGoogle Scholar
  50. Rolls BJ, Hetherington M, Laster LJ. Comparison of the effects of aspartame and sucrose on appetite and food intake. Appetite. 1988;11(Suppl 1):62–7.PubMedView ArticleGoogle Scholar
  51. Van Engelen M, Armstrong T, Rossiter M, Eskritt M, Bellissimo N. The effect of sugars in solution on subjective appetite and short-term food intake in normal weight boys. FASEB J. 2012;26Google Scholar
  52. Casperson SL, Johnson L, Roemmich JN. The relative reinforcing value of sweet versus savory snack foods after consumption of sugar- or non-nutritive sweetened beverages. Appetite. 2017;112:143–9.PubMedView ArticleGoogle Scholar
  53. Gadah NS, Brunstrom JM, Rogers PJ. Cross-over studies underestimate energy compensation: the example of sucrose-versus sucralose-containing drinks. Appetite. 2016;107:398–405.PubMedView ArticleGoogle Scholar
  54. Patel BP, Hamilton JK, Vien S, Thomas SG, Anderson GH. Pubertal status, pre-meal drink composition, and later meal timing interact in determining children's appetite and food intake. Appl Physiol Nutr Metab. 2016;41:924–30.PubMedView ArticleGoogle Scholar
  55. Sylvetsky AC, Brown RJ, Blau JE, Walter M, Rother KI. Hormonal responses to non-nutritive sweeteners in water and diet soda. Nutr Metab. 2016;13:71.View ArticleGoogle Scholar
  56. Tey SL, Salleh NB, Henry J, Forde CG. Effects of aspartame-, monk fruit-, stevia- and sucrose-sweetened beverages on postprandial glucose, insulin and energy intake. Int J Obes. 2017;41:450–7.View ArticleGoogle Scholar
  57. Black RM, Tanaka P, Leiter LA, Anderson GH. Soft drinks with aspartame: effect on subjective hunger, food selection, and food intake of young adult males. Physiol Behav 1991;49:803-10.Google Scholar
  58. Blackburn GL, Kanders BS, Lavin PT, Keller SD, Whatley J. The effect of aspartame as part of a multidisciplinary weight-control program on short- and long-term control of body weight. Am J Clin Nutr. 1997;65:409–18.PubMedGoogle Scholar
  59. Canty DJ, Chan MM. Effects of consumption of caloric vs noncaloric sweet drinks on indices of hunger and food consumption in normal adults. Am J Clin Nutr. 1991;53:1159–64.PubMedGoogle Scholar
  60. Drewnowski A, Massien C, Louis-Sylvestre J, Fricker J, Chapelot D, Apfelbaum M. Comparing the effects of aspartame and sucrose on motivational ratings, taste preferences, and energy intakes in humans. Am J Clin Nutr. 1994;59:338–45.PubMedGoogle Scholar
  61. Raben A, Moller BK, Flint A, Vasilaras TH, Moller AC, Holst JJ, Astrup A. Increased postprandial glycaemia, insulinemia, and lipidemia after 10 weeks' sucrose-rich diet compared to an artificially sweetened diet: a randomised controlled trial. Food Nutr Res. 2011;55Google Scholar
  62. Reid M, Hammersley R, Hill AJ, Skidmore P. Long-term dietary compensation for added sugar: effects of supplementary sucrose drinks over a 4-week period. Brit J Nutr. 2007;97:193–203.PubMedView ArticleGoogle Scholar
  63. Rolls BJ, Kim S, Fedoroff IC. Effects of drinks sweetened with sucrose or aspartame on hunger, thirst and food intake in men. Physiol Behav. 1990;48:19–26.PubMedView ArticleGoogle Scholar
  64. Ruyter JC, Olthof MO, Kuijper LDJ, Liem G, Seidell JC, Katan MB. Short-term satiety and long-term weight effects of sugarfree and sugar-sweetened beverages in children. Obesity facts. 2013;6:33.Google Scholar
  65. Mattes R. Effects of aspartame and sucrose on hunger and energy intake in humans. Physiol Behav. 1990;47:1037–44.PubMedView ArticleGoogle Scholar
  66. Ryan-Harshman M, Leiter LA, Anderson GH. Phenylalanine and aspartame fail to alter feeding behavior, mood and arousal in men. Physiol Behav. 1987;39:247–53.PubMedView ArticleGoogle Scholar
  67. Tordoff MG, Alleva AM. Effect of drinking soda sweetened with aspartame or high-fructose corn syrup on food intake and body weight. Am J Clin Nutr. 1990;51:963–9.PubMedGoogle Scholar
  68. Van Wymelbeke V, Beridot-Therond ME, de La Gueronniere V, Fantino M. Influence of repeated consumption of beverages containing sucrose or intense sweeteners on food intake. Eur J Clin Nutr. 2004;58:154–61.PubMedView ArticleGoogle Scholar
  69. Wilson JF. Lunch eating behavior of preschool children. Effects of age, gender, and type of beverage served. Physiol Behav. 2000;70:27–33.PubMedView ArticleGoogle Scholar
  70. Wilson JF. Does type of milk beverage affect lunchtime eating patterns and food choice by preschool children? Appetite. 1994;23:90–2.PubMedView ArticleGoogle Scholar
  71. Cullen M, Nolan J, Cullen M, Moloney M, Kearney J, Lambe J, Gibney MJ. Effect of high levels of intense sweetener intake in insulin dependent diabetics on the ratio of dietary sugar to fat: a case-control study. Eur J Clin Nutr. 2004;58:1336–41.PubMedView ArticleGoogle Scholar
  72. Gadah NS, Kyle LA, Smith JE, Brunstrom JM, Rogers PJ. No difference in compensation for sugar in a drink versus sugar in semi-solid and solid foods. Physiol Behav. 2016;156:35–42.PubMedView ArticleGoogle Scholar
  73. Hill SE, Prokosch ML, Morin A, Rodeheffer CD. The effect of non-caloric sweeteners on cognition, choice, and post-consumption satisfaction. Appetite. 2014;83:82–8.PubMedView ArticleGoogle Scholar
  74. Hammersley R, Reid M, Ballantyne C, Duffy M. Obese women partially compensate for sucrose added to the diet, without weight gain, over 28 days. Proc Nutr Soc. 2011;70(6):E384.View ArticleGoogle Scholar
  75. Porikos KP, Booth G, Van Itallie TB. Effect of covert nutritive dilution on the spontaneous food intake of obese individuals: a pilot study. Am J Clin Nutr. 1977;30:1638–44.PubMedGoogle Scholar
  76. Ballantyne CJ, Hammersley R, Reid M. Effects of sucrose added blind to the diet over eight weeks on body mass and mood in men. Appetite. 2011;57:S3.View ArticleGoogle Scholar
  77. Peters JC, Wyatt HR, Foster GD, Pan Z, Wojtanowski AC, Vander Veur SS, Herring SJ, Brill C, Hill JO. The effects of water and non-nutritive sweetened beverages on weight loss during a 12-week weight loss treatment program. Obesity (Silver Spring, Md). 2014;22:1415–21.View ArticleGoogle Scholar
  78. Piernas C, Tate DF, Xiaoshan W, Popkin BM. Does diet-beverage intake affect dietary consumption patterns? Results from the choose healthy options consciously everyday (CHOICE) randomized clinical trial. Am J Clin Nutr. 2013;97:604–11.PubMedPubMed CentralView ArticleGoogle Scholar
  79. Porikos KP, Hesser MF, van Itallie TB. Caloric regulation in normal-weight men maintained on a palatable diet of conventional foods. Physiol Behav. 1982;29:293–300.PubMedView ArticleGoogle Scholar
  80. Turner-McGrievy G, Wang X, Popkin B, Tate DF. Tasting profile affects adoption of caloric beverage reduction in a randomized weight loss intervention. Obes Sci Pract. 2016;2:392–8.PubMedPubMed CentralView ArticleGoogle Scholar
  81. Deighton K, Duckworth L, Matu J, Suter M, Fletcher C, Stead S, Ali S, Gunby N, Korsness K. Mouth rinsing with a sweet solution increases energy expenditure and decreases appetite during 60 min of self-regulated walking exercise. Appl Physiol Nutr Metab. 2016;41:1255–61.PubMedView ArticleGoogle Scholar
  82. Gibson SA, Horgan GW, Francis LE, Gibson AA, Stephen AM. Low calorie beverage consumption is associated with energy and nutrient intakes and diet quality in British adults. Nutrients. 2016;8:02.View ArticleGoogle Scholar
  83. Nissensohn M, Sánchez-Villegas A, Serra-Majem L. Beverage consumption habits amongst the Spanish population: association with total water and energy intake. Findings of the ANIBES study Revista de Neurologia. 2016;62:42.Google Scholar
  84. Berry C, Brusick D, Cohen SM, Hardisty JF, Grotz VL, Williams GM. Sucralose non-carcinogenicity: a review of the scientific and regulatory rationale. Nutr Cancer. 2016;68:1247–61.PubMedPubMed CentralView ArticleGoogle Scholar
  85. Olivier B, Serge AH, Catherine A, Jacques B, Murielle B, Marie-Chantal CL, Sybil C, Jean-Philippe G, Sabine H, Esther K, et al. Review of the nutritional benefits and risks related to intense sweeteners.[Erratum appears in Arch Public Health. 2015;73:49; PMID: 26500771]. Archives of Public Health. 2015;73:41.Google Scholar
  86. Andreatta MM, Munoz SE, Lantieri MJ, Eynard AR, Navarro A. Artificial sweetener consumption and urinary tract tumors in Cordoba. Argentina Prev Med. 2008;47:136–9.PubMedView ArticleGoogle Scholar
  87. Andreatta MM, Navarro A, Eynard AR. Urinary tract tumors, biology and risk for artificial sweeteners use with particular emphasis on some south American countries. Prev Med. 2008;4:185–95.Google Scholar
  88. Asal NR, Risser DR, Kadamani S, Geyer JR, Lee ET, Cherng N. Risk factors in renal cell carcinoma: I. Methodology, demographics, tobacco, beverage use, and obesity. Cancer Detect Prev. 1988;11:359–77.PubMedGoogle Scholar
  89. Bravo MP, Del Rey-Calero J, Conde M. Risk factors of bladder cancer in Spain. Neoplasma. 1987;34:633–7.PubMedGoogle Scholar
  90. Cartwright RA, Adib R, Glashan R, Gray BK. The epidemiology of bladder cancer in West Yorkshire. A preliminary report on non-occupational aetiologies. Carcinogenesis. 1981;2:343–7.PubMedView ArticleGoogle Scholar
  91. Hoover RN, Strasser PH. Artificial sweeteners and human bladder cancer. Preliminary results Lancet. 1980;1:837–40.PubMedView ArticleGoogle Scholar
  92. Howe GR, Burch JD, Miller AB, Cook GM, Esteve J, Morrison B, Gordon P, Chambers LW, Fodor G, Winsor GM. Tobacco use, occupation, coffee, various nutrients, and bladder cancer. J Natl Cancer Inst. 1980;64:701–13.PubMedGoogle Scholar
  93. Kantor AF, Hartge P, Hoover RN, Fraumeni JF Jr. Familial and environmental interactions in bladder cancer risk. Int J Cancer. 1985;35:703–6.PubMedView ArticleGoogle Scholar
  94. Mommsen S, Aagaard J, Sell A. A case-control study of female bladder cancer. Eur J Cancer Clin Oncol. 1983;19:725–9.PubMedView ArticleGoogle Scholar
  95. Sullivan JW. Epidemiologic survey of bladder cancer in greater New Orleans. J Urol. 1982;128:281–3.PubMedView ArticleGoogle Scholar
  96. Yu Y, Hu J, Wang PP, Zou Y, Qi Y, Zhao P, Xe R. Risk factors for bladder cancer: a case-control study in northeast China.[erratum appears in Eur J cancer Prev 1998 Apr;7(2):171]. Eur J Cancer Prev. 1997;6:363–9.PubMedView ArticleGoogle Scholar
  97. Connolly JG, Rider WD, Rosenbaum L, Chapman JA. Relation between the use of artificial sweeteners and bladder cancer. CMAJ. 1978;119:408.Google Scholar
  98. Goodman MT, Morgenstern H, Wynder EL. A case-control study of factors affecting the development of renal cell cancer. Am J Epidemiol. 1986;124:926–41.PubMedView ArticleGoogle Scholar
  99. Iscovich J, Castelletto R, Esteve J, Munoz N, Colanzi R, Coronel A, Deamezola I, Tassi V, Arslan A. Tobacco smoking, occupational exposure and bladder cancer in Argentina. Int J Cancer. 1987;40:734–40.PubMedView ArticleGoogle Scholar
  100. Kessler II, Clark JP. Saccharin, cyclamate, and human bladder cancer. No evidence of an association. JAMA. 1978;240:349–55.PubMedView ArticleGoogle Scholar
  101. Kobeissi LH, Yassine IA, Jabbour ME, Moussa MA, Dhaini HR. Urinary bladder cancer risk factors: a Lebanese case- control study. APJCP. 2013;14:3205–11.PubMedGoogle Scholar
  102. Moller-Jensen O, Knudsen JB, Sorensen BL, Clemmesen J. Artificial sweeteners and absence of bladder cancer risk in Copenhagen. Int J Cancer. 1983;32:577–82.PubMedView ArticleGoogle Scholar
  103. Momas I, Daures JP, Festy B, Bontoux J, Gremy F. Relative importance of risk factors in bladder carcinogenesis: some new results about Mediterranean habits. Cancer Causes Control. 1994;5:326–32.PubMedView ArticleGoogle Scholar
  104. Morgan RW, Jain MG. Bladder cancer: smoking, beverages and artificial sweeteners. CMAJ. 1974;111:1067–70.Google Scholar
  105. Morrison AS, Buring JE. Artificial sweeteners and cancer of the lower urinary tract. N Engl J Med. 1980;302:537–41.PubMedView ArticleGoogle Scholar
  106. Morrison AS, Verhoek WG, Leck I, Aoki K, Ohno Y, Obata K. Artificial sweeteners and bladder cancer in Manchester, U.K., and Nagoya, Japan. Br J Cancer. 1982;45:332–6.PubMedPubMed CentralView ArticleGoogle Scholar
  107. Najem GR, Louria DB, Seebode JJ, Thind IS, Prusakowski JM, Ambrose RB, Fernicola AR. Life time occupation, smoking, caffeine, saccharine, hair dyes and bladder carcinogenesis. Int J Epidemiol. 1982;11:212–7.PubMedView ArticleGoogle Scholar
  108. Nomura AM, Kolonel LN, Hankin JH, Yoshizawa CN. Dietary factors in cancer of the lower urinary tract. Int J Cancer. 1991;48:199–205.PubMedView ArticleGoogle Scholar
  109. Ohno Y, Aoki K, Obata K, Morrison AS. Case-control study of urinary bladder cancer in metropolitan Nagoya. Natl Cancer Inst Monogr. 1985;69:229–34.PubMedGoogle Scholar
  110. Radosavljevic V, Jankovic S, Marinkovic J, Djokic M. Some habits as risk factors for bladder cancer. J BUON. 2001;6:435–9.Google Scholar
  111. Risch HA, Burch JD, Miller AB, Hill GB, Steele R, Howe GR. Dietary factors and the incidence of cancer of the urinary bladder. Am J Epidemiol. 1988;127:1179–91.PubMedView ArticleGoogle Scholar
  112. Schulte PA, Ringen K, Hemstreet GP, Altekruse EB, Gullen WH, Tillett S, Allsbrook WC Jr, Crosby JH, Witherington R, Stringer W, et al. Risk factors for bladder cancer in a cohort exposed to aromatic amines. Cancer. 1986;58:2156–62.PubMedView ArticleGoogle Scholar
  113. Silverman DT, Hoover RN, Swanson GM. Artificial sweeteners and lower urinary tract cancer: hospital vs. population controls. Am J Epidemiol. 1983;117:326–34.PubMedView ArticleGoogle Scholar
  114. Simon D, Yen S, Cole P. Coffee drinking and cancer of the lower urinary tract. J Natl Cancer Inst. 1975;54:587–91.PubMedGoogle Scholar
  115. Wynder EL, Stellman SD. Artificial sweetener use and bladder cancer: a case-control study. Science. 1980;207:1214–6.PubMedView ArticleGoogle Scholar
  116. Walker AM, Dreyer NA, Friedlander E, Loughlin J, Rothman KJ, Kohn HI. An independent analysis of the National Cancer Institute study on non-nutritive sweeteners and bladder cancer. Am J Public Health. 1982;72:376–81.PubMedPubMed CentralView ArticleGoogle Scholar
  117. Cabaniols C, Giorgi R, Chinot O, Ferahta N, Spinelli V, Alla P, Barrie M, Lehucher-Michel MP. Links between private habits, psychological stress and brain cancer: a case-control pilot study in France. J Neuro-Oncol. 2011;103:307–16.View ArticleGoogle Scholar
  118. Gurney JG, Pogoda JM, Holly EA, Hecht SS, Preston-Martin S. Aspartame consumption in relation to childhood brain tumor risk: results from a case-control study.[Erratum appears in J Natl Cancer Inst 1997 Oct 1;89(19):1460]. 1997;89:1072–4.Google Scholar
  119. Mahfouz EM, Sadek RR, Abdel-Latief WM, Mosallem FA, Hassan EE. The role of dietary and lifestyle factors in the development of colorectal cancer: case control study in Minia. Egypt Cent Eur J Public Health. 2014;22:215–22.PubMedView ArticleGoogle Scholar
  120. Norell SE, Ahlbom A, Erwald R, Jacobson G, Lindberg-Navier I, Olin R, Tornberg B, Wiechel KL. Diet and pancreatic cancer: a case-control study. Am J Epidemiol. 1986;124:894–902.PubMedView ArticleGoogle Scholar
  121. Chan JM, Wang F, Holly EA. Sweets, sweetened beverages, and risk of pancreatic cancer in a large population-based case-control study. Cancer Causes Control. 2009;20:835–46.PubMedPubMed CentralView ArticleGoogle Scholar
  122. Ewertz M, Gill C. Dietary factors and breast-cancer risk in Denmark. Int J Cancer. 1990;46:779–84.PubMedView ArticleGoogle Scholar
  123. Gallus S, Scotti L, Negri E, Talamini R, Franceschi S, Montella M, Giacosa A, Dal Maso L, La Vecchia C. Artificial sweeteners and cancer risk in a network of case-control studies. Ann Oncol. 2007;18:40–4.PubMedView ArticleGoogle Scholar
  124. Morrison AS. Use of artificial sweeteners by cancer patients. J Natl Cancer Inst. 1979;62:1397–9.PubMedGoogle Scholar
  125. Bosetti C, Gallus S, Talamini R, Montella M, Franceschi S, Negri E, La Vecchia C. Artificial sweeteners and the risk of gastric, pancreatic, and endometrial cancers in Italy. Cancer Epidemiol Biomark Prev. 2009;18:2235–8.View ArticleGoogle Scholar
  126. Akdas A, Kirkali Z, Bilir N. Epidemiological case-control study on the etiology of bladder cancer in Turkey. Eur Urol. 1990;17:23–6.PubMedGoogle Scholar
  127. McCullough ML, Teras LR, Shah R, Diver WR, Gaudet MM, Gapstur SM. Artificially and sugar-sweetened carbonated beverage consumption is not associated with risk of lymphoid neoplasms in older men and women. J Nutr. 2014;144:2041–9.PubMedView ArticleGoogle Scholar
  128. Lim U, Subar AF, Mouw T, Hartge P, Morton LM, Stolzenberg-Solomon R, Campbell D, Hollenbeck AR, Schatzkin A. Consumption of aspartame-containing beverages and incidence of hematopoietic and brain malignancies. Cancer Epidemiol Biomark Prev. 2006;15:1654–9.View ArticleGoogle Scholar
  129. Stepien M, Duarte-Salles T, Fedirko V, Trichopoulou A, Lagiou P, Bamia C, Overvad K, Tjonneland A, Hansen L, Boutron-Ruault MC, et al. Consumption of soft drinks and juices and risk of liver and biliary tract cancers in a European cohort. Eur J Nutr. 2016;55:7–20.PubMedView ArticleGoogle Scholar
  130. Armstrong B, Lea AJ, Adelstein AM, Donovan JW, White GC, Ruttle S. Cancer mortality and saccharin consumption in diabetics. BMJ. 1976;30:151–7.Google Scholar
  131. Koch M, Hill GB, McPhee MS. Factors affecting recurrence rates in superficial bladder cancer. J Natl Cancer Inst. 1986;76:1025–9.PubMedGoogle Scholar
  132. Wakai K, Ohno Y, Obata K, Aoki K. Prognostic significance of selected lifestyle factors in urinary bladder cancer. Jpn J Cancer Res. 1993;84:1223–9.PubMedView ArticleGoogle Scholar
  133. Jensen OM, Kamby C. Intra-uterine exposure to saccharin and risk of bladder cancer in man. Int J Cancer. 1982;29:507–9.PubMedView ArticleGoogle Scholar
  134. Lay WA, Vickery CR, Ward-Ritacco CL, Johnson KB, Berg AC, Evans EM, Johnson MA. Comparison of intake of animal and plant foods and related nutrients in postmenopausal breast cancer survivors and controls. J Nutr Gerontol Geriatr. 2016;35:15–31.PubMedView ArticleGoogle Scholar
  135. Cheungpasitporn W, Thongprayoon C, O'Corragain OA, Edmonds PJ, Kittanamongkolchai W, Erickson SB. Associations of sugar-sweetened and artificially sweetened soda with chronic kidney disease: a systematic review and meta-analysis. Nephrol. 2014;19:791–7.View ArticleGoogle Scholar
  136. Bomback AS, Derebail VK, Shoham DA, Anderson CA, Steffen LM, Rosamond WD, Kshirsagar AV. Sugar-sweetened soda consumption, hyperuricemia, and kidney disease. Kidney Int. 2010;77:609–16.PubMedView ArticleGoogle Scholar
  137. Bomback AS, Katz R, He K, Shoham DA, Burke GL, Klemmer PJ. Sugar-sweetened beverage consumption and the progression of chronic kidney disease in the multi-ethnic study of atherosclerosis (MESA). Am J Clin Nutr. 2009;90:1172–8.PubMedPubMed CentralView ArticleGoogle Scholar
  138. Lin J, Curhan GC. Associations of sugar and artificially sweetened soda with albuminuria and kidney function decline in women. Clin J Am Soc Nephrol. 2011;6:160–6.PubMedPubMed CentralView ArticleGoogle Scholar
  139. Saldana TM, Basso O, Darden R, Sandler DP. Carbonated beverages and chronic kidney disease. Epidemiology (Cambridge, Mass). 2007;18:501–6.View ArticleGoogle Scholar
  140. Shoham DA, Durazo-Arvizu R, Kramer H, Luke A, Vupputuri S, Kshirsagar A, Cooper RS. Sugary soda consumption and albuminuria: results from the National Health and nutrition examination survey, 1999-2004. PLoS One. 2008;3:e3431.PubMedPubMed CentralView ArticleGoogle Scholar
  141. Beiswanger BB, Boneta AE, Mau MS, Katz BP, Proskin HM, Stookey GK. The effect of chewing sugar-free gum after meals on clinical caries incidence. JADA. 1998;129:1623–6.PubMedGoogle Scholar
  142. Lopez de Bocanera ME, Koss de Stisman MA, Bru de Labanda E, Chervonagura de Gepner A. Statistical analysis of salivary pH changes after the intake of black tea and yerba mate supplemented with sweeteners. J Oral Science. 1999;41:81–5.View ArticleGoogle Scholar
  143. Brambilla E, Cagetti MG, Ionescu A, Campus G, Lingstrom P. An in vitro and in vivo comparison of the effect of Stevia Rebaudiana extracts on different caries-related variables: a randomized controlled trial pilot study. Caries Res. 2014;48:19–23.PubMedView ArticleGoogle Scholar
  144. Jawale BA, Bendgude V, Mahuli AV, Dave B, Kulkarni H, Mittal S. Dental plaque pH variation with regular soft drink, diet soft drink and high energy drink: an in vivo study. J Contemp Dent Pract. 2012;13:201–4.PubMedGoogle Scholar
  145. Manning RH, Edgar WM. pH changes in plaque after eating snacks and meals, and their modification by chewing sugared- or sugar-free gum. Br Dent J. 1993;174:241–4.PubMedView ArticleGoogle Scholar
  146. Mendes de Santana Giongo FC, Mua B, Fatturi Parolo CC, Carlen A, Maltz M. Effects of lactose-containing stevioside sweeteners on dental biofilm acidogenicity. Brazilian Oral Research. 2014;28:249–54.Google Scholar
  147. Mentes A. pH changes in dental plaque after using sugar-free pediatric medicine. J Clin Pediatr Dent. 2001;25:307–12.PubMedView ArticleGoogle Scholar
  148. Meyerowitz C, Syrrakou EP, Raubertas RF. Effect of sucralose--alone or bulked with maltodextrin and/or dextrose--on plaque pH in humans. Caries Res. 1996;30:439–44.PubMedView ArticleGoogle Scholar
  149. Park K, Schemehorn B, Garcia N, Stookey G, Kim T, Hovliaris C. Effect of sucralose chewing gum on plaque pH response [abstract]. J Dent Res. 1993;72:397. Abstract no: 2347Google Scholar
  150. Park KK, Hernandez D, Schemehorn BR, Katz BP, Stookey GK, Sanders PG, Butchko HH. Effect of chewing gums on plaque pH after a sucrose challenge. ASDC J Dent Child. 1995;62:180–6.PubMedGoogle Scholar
  151. Roos EH, Donly KJ. In vivo dental plaque pH variation with regular and diet soft drinks. Pediatr Dent. 2002;24:350–3.PubMedGoogle Scholar
  152. Steinberg LM, Odusola F, Yip J, Mandel ID. Effect of aqueous solutions of sucralose on plaque pH. Am J Dent. 1995;8:209–11.PubMedGoogle Scholar
  153. Steinberg LM, Odusola F, Mandel ID. Effect of sucralose in coffee on plaque pH in human subjects. Caries Res. 1996;30:138–42.PubMedView ArticleGoogle Scholar
  154. Zanela NL, Bijella MF, Rosa OP. The influence of mouthrinses with antimicrobial solutions on the inhibition of dental plaque and on the levels of mutans streptococci in children. Pesqui Odontol Bras. 2002;16:101–6.PubMedView ArticleGoogle Scholar
  155. Muhlemann M, Graf H. 'Harmless-To-teeth' properties of the sugar substitute aspartame and 3 aspartame-containing products: Canderal tablets--Canderal powder concentrate--Canderal sweetener powder. Swiss Dent. 1985;6:25–7.PubMedGoogle Scholar
  156. Syrrakou EP, Meyerowitz C, Raubertas RF. The effect of Sucralose on plaque pH (IADR abstract). J Dent Res. 1993;72Google Scholar
  157. Greenwood DC, Threapleton DE, Evans CEL, Cleghorn CL, Nykjaer C, Woodhead C, Burley VJ. Association between sugar-sweetened and artificially sweetened soft drinks and type 2 diabetes: systematic review and dose-response meta-analysis of prospective studies. Brit J Nutr. 2014;112:725–34.PubMedView ArticleGoogle Scholar
  158. Nettleton JA, Lutsey PL, Wang Y, Lima JA, Michos ED, Jacobs DR Jr. Diet soda intake and risk of incident metabolic syndrome and type 2 diabetes in the multi-ethnic study of atherosclerosis (MESA). Diabetes Care. 2009;32:688–94.PubMedPubMed CentralView ArticleGoogle Scholar
  159. Lutsey PL, Steffen LM, Stevens J. Dietary intake and the development of the metabolic syndrome: the atherosclerosis risk in communities study. Circulation. 2008;117:754–61.PubMedView ArticleGoogle Scholar
  160. De Koning L, Malik VS, Rimm EB, Willett WC, Hu FB. Sugar-sweetened and artificially sweetened beverage consumption and risk of type 2 diabetes in men. Am J Clin Nutr. 2011;93:1321–7.PubMedPubMed CentralView ArticleGoogle Scholar
  161. Imamura F, O'Connor L, Ye Z, Mursu J, Hayashino Y, Bhupathiraju SN, Forouhi NG. Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: systematic review, meta-analysis, and estimation of population attributable fraction. Brit J Sports Med. 2016;50:496–504.View ArticleGoogle Scholar
  162. Fagherazzi G, Vilier A, Saes Sartorelli D, Lajous M, Balkau B, Clavel-Chapelon F. Consumption of artificially and sugar-sweetened beverages and incident type 2 diabetes in the etude Epidemiologique aupres des femmes de la Mutuelle Generale de l'Education Nationale-European prospective investigation into cancer and nutrition cohort. Am J Clin Nutr. 2013;97:517–23.PubMedView ArticleGoogle Scholar
  163. Fagherazzi G, Gusto G, Affret A, Mancini FR, Dow C, Balkau B, Clavel-Chapelon F, Bonnet F, Boutron-Ruault MC. Chronic consumption of artificial sweetener in packets or tablets and type 2 diabetes risk: evidence from the E3N-European prospective investigation into cancer and nutrition study. Ann Nutr Metab. 2017;70:51–8.PubMedView ArticleGoogle Scholar
  164. InterAct C, Romaguera D, Norat T, Wark PA, Vergnaud AC, Schulze MB, van Woudenbergh GJ, Drogan D, Amiano P, Molina-Montes E, et al. Consumption of sweet beverages and type 2 diabetes incidence in European adults: results from EPIC-InterAct. Diabet. 2013;56:1520–30.View ArticleGoogle Scholar
  165. Bhupathiraju SN, Pan A, Malik VS, Manson JE, Willett WC, van Dam RM, Hu FB. Caffeinated and caffeine-free beverages and risk of type 2 diabetes. Am J Clin Nutr. 2013;97:155–66.PubMedView ArticleGoogle Scholar
  166. Armstrong B, Doll R. Bladder cancer mortality in diabetics in relation to saccharin consumption and smoking habits. Br J Prev Soc Med. 1975;29:73–81.PubMedPubMed CentralGoogle Scholar
  167. Eeden SK, Koepsell TD, Longstreth WT, Belle G, Daling JR, McKnight B. Aspartame ingestion and headaches: a randomized crossover trial. Neurology. 1994;44:1787–93.PubMedView ArticleGoogle Scholar
  168. Koehler SM, Glaros A. The effect of aspartame on migraine headache. Headache. 1988;28:10–4.PubMedView ArticleGoogle Scholar
  169. Schiffman S. Aspartame and headache: No association found in clinical study. N Engl J Med. 1989;9:101–2.Google Scholar
  170. Lipton RB, Newman LC, Cohen JS, Solomon S. Aspartame as a dietary trigger of headache. Headache. 1989;29:90–2.PubMedView ArticleGoogle Scholar
  171. Taheri S. To study the significance of dietary trigger factors and their exclusion in the aetiology and treatment of childhood headache disorders. Cephalalgia. 2011;31:202.Google Scholar
  172. Lindseth GN, Coolahan SE, Petros TV, Lindseth PD. Neurobehavioral effects of aspartame consumption. Res Nurs Health. 2014;37:185–93.PubMedView ArticleGoogle Scholar
  173. Guo X, Park Y, Freedman ND, Sinha R, Hollenbeck AR, Blair A, Chen H. Sweetened beverages, coffee, and tea and depression risk among older US adults. PLoS One. 2014;9:e94715.PubMedPubMed CentralView ArticleGoogle Scholar
  174. Walton RG, Hudak R, Green-Waite RJ. Adverse reactions to aspartame: double-blind challenge in patients from a vulnerable population. Biol Psychiatry. 1993;34:13–7.PubMedView ArticleGoogle Scholar
  175. Baker FM, Jordan B, Barclay L, Schoenberg BS. Risk factors for clinically diagnosed Alzheimer's disease. Int J Geriatr Psychiatry. 1993;8:379–85.View ArticleGoogle Scholar
  176. Halldorsson TI, Strøm M, Petersen SB, Olsen SF. Intake of artificially sweetened soft drinks and risk of preterm delivery: a prospective cohort study in 59,334 Danish pregnant women. Am J Clin Nutr. 2010;92:626–33.PubMedView ArticleGoogle Scholar
  177. Englund-Ogge L, Brantsaeter AL, Haugen M, Sellgpiel V, Khatibi A, Myhre R, Myking S, Meltzer HM, Kacerovsky M, Nilsen RM, Jacobsson B. Association between intake of artificially sweetened and sugar-sweetened beverages and preterm delivery: a large prospective cohort study. Am J Clin Nutr. 2012;96:552–9.PubMedPubMed CentralView ArticleGoogle Scholar
  178. Petherick ES, Goran MI, Wright J. Relationship between artificially sweetened and sugar-sweetened cola beverage consumption during pregnancy and preterm delivery in a multi-ethnic cohort: analysis of the born in Bradford cohort study. Eur J Clin Nutr. 2014;68:404–7.PubMedView ArticleGoogle Scholar
  179. Kline J, Stein ZA, Susser M, Warburton D. Spontaneous abortion and the use of sugar substitutes (saccharin). Am J Obstet Gynecol. 1978;130:708–11.PubMedView ArticleGoogle Scholar
  180. Pereira MA. Sugar-sweetened and artificially-sweetened beverages in relation to obesity risk. Adv Nutr. 2014;5:797–808.PubMedPubMed CentralView ArticleGoogle Scholar
  181. Miller PE, Perez V. Low-calorie sweeteners and body weight and composition: a meta-analysis of randomized controlled trials and prospective cohort studies. Am J Clin Nutr. 2014;100:765–77.PubMedPubMed CentralView ArticleGoogle Scholar
  182. Rogers PJ, Hogenkamp PS, De Graaf C, Higgs S, Lluch A, Ness AR, Penfold C, Perry R, Putz P, Yeomans MR, Mela DJ. Does low-energy sweetener consumption affect energy intake and body weight? A systematic review, including meta-analyses, of the evidence from human and animal studies. Int J Obes. 2016;40:381–94.View ArticleGoogle Scholar
  183. Reid AE, Chauhan BF, Rabbani R, Lys J, Copstein L, Mann A, Abou-Setta AM, Fiander M, MacKay DS, McGavock J, et al. Early exposure to nonnutritive sweeteners and long-term metabolic health: a systematic review. Pediatrics. 2016;137Google Scholar
  184. de Ruyter JC, Olthof MR, Seidell JC, Katan MB. A trial of sugar-free or sugar-sweetened beverages and body weight in children. N Engl J Med. 2012;367:1397–406.PubMedView ArticleGoogle Scholar
  185. Ebbeling CB, Feldman HA, Chomitz VR, Antonelli TA, Gortmaker SL, Osganian SK, Ludwig DS. A randomized trial of sugar-sweetened beverages and adolescent body weight. N Engl J Med. 2012;367:1407–16.PubMedPubMed CentralView ArticleGoogle Scholar
  186. Ebbeling CB, Feldman HA, Osganian SK, Chomitz VR, Ellenbogen SJ, Ludwig DS. Effects of decreasing sugar-sweetened beverage consumption on body weight in adolescents: a randomized, controlled pilot study. Pediatrics. 2006;117:673–80.PubMedView ArticleGoogle Scholar
  187. Hsieh M-H, Chan P, Sue Y-M, Liu J-C, Liang TH, Huang T-Y, Tomlinson B, Chow MSS, Kao P-F, Chen Y-J. Efficacy and tolerability of oral stevioside in patients with mild essential hypertension: a two-year, randomized, placebo-controlled study. Clin Ther. 2003;25:2797–808.PubMedView ArticleGoogle Scholar
  188. Kanders BS, Lavin PT, Kowalchuk MB, Greenberg I, Blackburn GL. An evaluation of the effect of aspartame on weight loss. Appetite. 1988;11(Suppl 1):73–84.PubMedView ArticleGoogle Scholar
  189. Kim EJ, Kim MY, Kim JS, Cho KD, Han CK, Lee BH. Effects of fructooligosaccharides intake on body weight, lipid profiles, and calcium status among Korean college students. FASEB J. 2011;25Google Scholar
  190. Knopp RH, Brandt K, Arky RA. Effects of aspartame in young persons during weight reduction. J Toxicol Environ Health. 1976;2:417–28.PubMedView ArticleGoogle Scholar
  191. Leon AS, Hunninghake DB, Bell C, Rassin DK, Tephly TR. Safety of long-term large doses of aspartame. Arch Intern Med. 1989;149:2318–24.PubMedView ArticleGoogle Scholar
  192. Maersk M, Belza A, Stodkilde-Jorgensen H, Ringgaard S, Chabanova E, Thomsen H, Pedersen SB, Astrup A, Richelsen B. Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study. Am J Clin Nutr. 2012;95:283–9.PubMedView ArticleGoogle Scholar
  193. Maki KC, Curry LL, Reeves MS, Toth PD, McKenney JM, Farmer MV, Schwartz SL, Lubin BC, Boileau AC, Dicklin MR, et al. Chronic consumption of rebaudioside a, a steviol glycoside, in men and women with type 2 diabetes mellitus. Food Chem Tox. 2008;46(Suppl 7):S47–53.View ArticleGoogle Scholar
  194. Marisela Vazquez Duran M, Castillo Martinez L, Orea Tejada A, Tellez Olvera DA, Delgado Perez LG, Marquez Zepeda B, Pineda Juarez JA, Lopez Rodriguez Y. Effect of decreasing the consumption of sweetened caloric and non-caloric beverages on weight, body composition and blood pressure in young adults. Eur J Prev Cardiol. 2013;1:S120.Google Scholar
  195. Peters JC, Beck J, Cardel M, Wyatt HR, Foster GD, Pan Z, Wojtanowski AC, Vander Veur SS, Herring SJ, Brill C, Hill JO. The effects of water and non-nutritive sweetened beverages on weight loss and weight maintenance: a randomized clinical trial. Obesity. 2016;24:297–304.PubMedView ArticleGoogle Scholar
  196. Raben A, Moller AC, Vasilaras TH, Astrup A. A randomized 10 week trial of sucrose vs artificial sweeteners on body weight and blood pressure after 10 weeks [abstract]. Obes Res. 2001;9:86s.View ArticleGoogle Scholar
  197. Reid M, Hammersley R, Duffy M. Effects of sucrose drinks on macronutrient intake, body weight, and mood state in overweight women over 4 weeks. Appetite. 2010;55:130–6.PubMedView ArticleGoogle Scholar
  198. Reyna NY, Cano C, Bermúdez VJ, Medina MT, Souki AJ, Ambard M, Nuñez M, Ferrer MA, Inglett GE. Sweeteners and beta-glucans improve metabolic and anthropometrics variables in well controlled type 2 diabetic patients. Am J Ther. 2003;10:438–43.PubMedView ArticleGoogle Scholar
  199. Rodearmel SJ, Wyatt HR, Stroebele N, Smith SM, Ogden LG, Hill JO. Small changes in dietary sugar and physical activity as an approach to preventing excessive weight gain: the America on the move family study. Obes Res. 2007;120:e869–79.Google Scholar
  200. Sørensen LB, Vasilaras TH, Astrup A, Raben A. Sucrose compared with artificial sweeteners: a clinical intervention study of effects on energy intake, appetite, and energy expenditure after 10 wk of supplementation in overweight subjects. Am J Clin Nutr. 2014;100:36–45.PubMedView ArticleGoogle Scholar
  201. Williams CL, Strobino BA, Brotanek J. Weight control among obese adolescents: a pilot study. Int J Food Sci Nutr. 2007;58:217–30.PubMedView ArticleGoogle Scholar
  202. French SA, Sherwood NE, JaKa MM, Haapala JL, Ebbeling CB, Ludwig DS. Physical changes in the home environment to reduce television viewing and sugar-sweetened beverage consumption among 5- to 12-year-old children: a randomized pilot study. Pediatric Obesity. 2016;11:e12–e5.PubMedView ArticleGoogle Scholar
  203. Markey O, Le Jeune J, Lovegrove JA. Energy compensation following consumption of sugar-reduced products: a randomized controlled trial. Eur J Nutr. 2016;55:2137–49.PubMedView ArticleGoogle Scholar
  204. Kassi EN, Landis G, Pavlaki A, Lambrou G, Mantzou E, Androulakis I, Giannakou A, Papanikolaou E, Chrousos GP. Long-term effects of stevia rebaudiana on glucose and lipid profile, adipocytokines, markers of inflammation and oxidation status in patients with metabolic syndrome. Endocr Rev. 2016;37.Google Scholar
  205. Vazquez-Duran M, Orea-Tejeda A, Castillo-Martinez L, Cano-Garcia A, Tellez-Olvera L, Keirns-Davis C. A randomized control trial for reduction of caloric and non-caloric sweetened beverages in young adults: effects in weight, body composition and blood pressure. Nutr Hosp. 2016;33:1372–8.PubMedView ArticleGoogle Scholar
  206. Shin DH, Lee JH, Kang MS, Kim TH, Jeong SJ, Kim CH, Kim SS, Kim IJ. Glycemic effects of rebaudioside a and erythritol in people with glucose intolerance. Diabetes Metab J. 2016;40:283–9.PubMedPubMed CentralView ArticleGoogle Scholar
  207. Berkey CS, Rockett HR, Field AE, Gillman MW, Colditz GA. Sugar-added beverages and adolescent weight change. Obes Res. 2004;12:778–88.PubMedView ArticleGoogle Scholar
  208. Chen L, Appel LJ, Loria C, Lin PH, Champagne CM, Elmer PJ, Ard JD, Mitchell D, Batch BC, Svetkey LP, Caballero B. Reduction in consumption of sugar-sweetened beverages is associated with weight loss: the PREMIER trial. Am J Clin Nutr. 2009;89:1299–306.PubMedPubMed CentralView ArticleGoogle Scholar
  209. Colditz GA, Willett WC, Stampfer MJ, London SJ, Segal MR, Speizer FE. Patterns of weight change and their relation to diet in a cohort of healthy women. Am J Clin Nutr. 1990;51:1100–5.PubMedGoogle Scholar
  210. Fowler SP, Williams K, Resendez RG, Hunt KJ, Hazuda HP, Stern MP. Fueling the obesity epidemic? Artificially sweetened beverage use and long-term weight gain. Obes J. 2008;16:1894–900.View ArticleGoogle Scholar
  211. Fowler SP, Williams K, Hazuda HP. Diet soda intake is associated with long-term increases in waist circumference in a biethnic cohort of older adults: the San Antonio longitudinal study of aging. J Am Geriatr Soc. 2015;63:708–15.PubMedPubMed CentralView ArticleGoogle Scholar
  212. Kral TVE, Stunkard AJ, Berkowitz RI, Stallings VA, Moore RH, Faith MS. Beverage consumption patterns of children born at different risk of obesity. Obesity. 2008;16:1802–8.PubMedPubMed CentralView ArticleGoogle Scholar
  213. Ludwig DS, Peterson KE, Gortmaker SL. Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet. 2001;357:505–8.PubMedView ArticleGoogle Scholar
  214. Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med. 2011;364:2392–404.PubMedPubMed CentralView ArticleGoogle Scholar
  215. Pan A, Malik VS, Hao T, Willett WC, Mozaffarian D, Hu FB. Changes in water and beverage intake and long-term weight changes: results from three prospective cohort studies. Int J Obes. 2013;37:1378–85.View ArticleGoogle Scholar
  216. Parker DR, Gonzalez S, Derby CA, Gans KM, Lasater TM, Carleton RA. Dietary factors in relation to weight change among men and women from two southeastern New England communities. Int J Obes. 1997;21:103–9.View ArticleGoogle Scholar
  217. Schulze MB, Manson JE, Ludwig DS, Colditz GA, Stampfer MJ, Willett WC, Hu FB. Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in young and middle-aged women. J Am Med Assoc. 2004;292:927–34.View ArticleGoogle Scholar
  218. Stellman SD, Garfinkel L. Artificial sweetener use and one-year weight change among women. Prev Med. 1986;15:195–202.PubMedView ArticleGoogle Scholar
  219. Striegel-Moore RH, Thompson D, Affenito SG, Franko DL, Obarzanek E, Barton BA, Schreiber GB, Daniels SR, Schmidt M, Crawford PB. Correlates of beverage intake in adolescent girls: the National Heart, Lung, and Blood Institute growth and health study. J Ped. 2006;148:183–7.View ArticleGoogle Scholar
  220. Vanselow MS, Pereira MA, Neumark-Sztainer D, Raatz SK. Adolescent beverage habits and changes in weight over time: findings from project EAT. Am J Clin Nutr. 2009;90:1489–95.PubMedView ArticleGoogle Scholar
  221. Aguero SD, Onate G, Rivera PH. Consumption of non-nutritive sweeteners and nutritional status in 10-16 year old students. Arch Argent Pediatr. 2014;112:207–14.Google Scholar
  222. Cancer Prevention Study II. The American Cancer Society Prospective Study. Stat Bull Metrop Insur Co. 1992;73:21–9.Google Scholar
  223. Bellisle F, De Altenburg Assis MA, Fieux B, Preziosi P, Galan P, Guy-Grand B, Hercberg S. Use of 'light' foods and drinks in French adults: biological, anthropometric and nutritional correlates. J Hum Nutr Diet. 2001;14:191–206.PubMedView ArticleGoogle Scholar
  224. Blum JW, Jacobsen DJ, Donnelly JE. Beverage consumption patterns in elementary school aged children across a two-year period. J Am Coll Nutr. 2005;24:93–8.PubMedView ArticleGoogle Scholar
  225. Bouchard DR, Ross R, Janssen I. Coffee, tea and their additives: association with BMI and waist circumference. Obesity Facts. 2010;3:345–52.PubMedView ArticleGoogle Scholar
  226. Crichton G, Alkerwi A, Elias M. Diet soft drink consumption is associated with the metabolic syndrome: a two sample comparison. Nutrients. 2015;7:3569–86.PubMedPubMed CentralView ArticleGoogle Scholar
  227. Duran Aguero S, Blanco Batten E, Rodriguez Noel Mdel P, Cordon Arrivillaga K, Salazar de Ariza J, Record Cornwall J, Cereceda Bujaico Mdel P, Antezana Almorza S, Espinoza Bernardo S, Encina Vega C. Association between non-nutritive sweeteners and obesity risk among university students in Latin America. Revista Medica de Chile. 2015;143:367–73.PubMedView ArticleGoogle Scholar
  228. Durán Agüero S, Vásquez Leiva A, Morales Illanes G, Schifferli Castro I, Sanhueza Espinoza C, Encina Vega C, Vivanco Cuevas K, Mena Bolvaran R. ASSOCIATION BETWEEN STEVIA SWEETENER CONSUMPTION AND NUTRITIONAL STATUS IN UNIVERSITY STUDENTS. Nutr Hosp. 2015;32:362–6.PubMedGoogle Scholar
  229. Forshee RA, Storey ML. Total beverage consumption and beverage choices among children and adolescents. Int J Food Sci Nutr. 2003;54:297–307.PubMedView ArticleGoogle Scholar
  230. Garcia-Meseguer MJ, Cervera Burriel F, Vico Garcia C, Milla Tobarra M, Serrano UR. Consumption of non caloric sweeteners in university population. Ann Nutr Metab. 2013;63:1103.Google Scholar
  231. Geraldo APG, Pinto ESMEM. Factors associated with diet soda consumption by employees of public universities in Sao Paulo state (Brazil). Obes Facts. 2013;6:150–1.Google Scholar
  232. Giammattei J, Blix G, Marshak HH, Wollitzer AO, Pettitt DJ. Television watching and soft drink consumption: associations with obesity in 11- to 13-year-old schoolchildren. Arch Pediatr Adolesc Med. 2003;157:882–6.PubMedView ArticleGoogle Scholar
  233. Ledoux TA, Watson K, Barnett A, Nguyen NT, Baranowski JC, Baranowski T. Components of the diet associated with child adiposity: a cross-sectional study. J Am Coll Nutr. 2011;30:536–46.PubMedView ArticleGoogle Scholar
  234. O'Connor TM, Yang SJ, Nicklas TA. Beverage intake among preschool children and its effect on weight status. Pediatrics. 2006;118:e1010–8.PubMedView ArticleGoogle Scholar
  235. Serra-Majem L, Ribas L, Ingles C, Fuentes M, Lloveras G, Salleras L. Cyclamate consumption in Catalonia, Spain (1992): relationship with the body mass index. Food Addit Contam. 1996;13:695–703.PubMedView ArticleGoogle Scholar
  236. Appleton KM, Conner MT. Body weight, body-weight concerns and eating styles in habitual heavy users and non-users of artificially sweetened beverages. Appetite. 2001;37:225–30.PubMedView ArticleGoogle Scholar
  237. Chia CW, Shardell M, Tanaka T, Liu DD, Gravenstein KS, Simonsick EM, Egan JM, Ferrucci L. Chronic low-calorie sweetener use and risk of abdominal obesity among older adults: a cohort study. PLoS One. 2016;11Google Scholar
  238. Drewnowski A, Rehm CD. The use of low-calorie sweeteners is associated with self-reported prior intent to lose weight in a representative sample of US adults. Nutr Diab. 2016;6Google Scholar
  239. Azad MB, Sharma AK, de Souza RJ, Dolinsky VW, Becker AB, Mandhane PJ, Turvey SE, Subbarao P, Lefebvre DL, Sears MR, Canadian Healthy Infant Longitudinal Development Study I. Association between artificially sweetened beverage consumption during pregnancy and infant body mass index. JAMA Pediatr. 2016;170:662–70.PubMedView ArticleGoogle Scholar
  240. Kuk JL, Brown RE. Aspartame intake is associated with greater glucose intolerance in individuals with obesity. Appl Physiol Nutr Metab. 2016;41:795–8.PubMedView ArticleGoogle Scholar
  241. Wulaningsih W, Van Hemelrijck M, Tsilidis KK, Tzoulaki I, Patel C, Rohrmann S. Investigating nutrition and lifestyle factors as determinants of abdominal obesity: an environment-wide study. Int J Obes. 2017;41:340–7.View ArticleGoogle Scholar
  242. Maki KC, Curry LL, Carakostas MC, Tarka SM, Reeves MS, Farmer MV, McKenney JM, Toth PD, Schwartz SL, Lubin BC, et al. The hemodynamic effects of rebaudioside a in healthy adults with normal and low-normal blood pressure. Food Chem Toxicol. 2008;46(Suppl 7):S40–6.PubMedView ArticleGoogle Scholar
  243. Grotz VL, Henry RR, McGill JB, Prince MJ, Shamoon H, Trout JR, Pi-Sunyer X. Lack of effect of sucralose on glucose homeostasis in subjects with type 2 diabetes. J Am Diet Assoc. 2003;103:1607–12.PubMedView ArticleGoogle Scholar
  244. Horwitz DL, McLane M, Kobe P. Response to single dose of aspartame or saccharin by NIDDM patients. Diab Care. 1988;11:230–4.View ArticleGoogle Scholar
  245. Olalde-Mendoza L, Moreno-Gonzalez YE. Modification of fasting blood glucose in adults with diabetes mellitus type 2 after regular soda and diet soda intake in the state of Queretaro, Mexico. Arch Latinoam Nutr. 2013;63:142–7.PubMedGoogle Scholar
  246. Stern SB, Bleicher SJ, Flores A, Gombos G, Recitas D, Shu J. Administration of aspartame in non-insulin-dependent diabetics. J Toxicol Environ Health. 1976;2:429–39.PubMedView ArticleGoogle Scholar
  247. Koyuncu BU, Balcı MK. Metabolic effects of dissolved aspartame in the mouth before meals in prediabetic patients; a randomized controlled cross-over study. J Endocrinol Diabetes Obes. 2014;2:1032.Google Scholar
  248. Chantelau EA, Gosseringer G, Sonnenberg GE, Berger M. Moderate intake of sucrose does not impair metabolic control in pump-treated diabetic out-patients. Diabetologia. 1985;28:204–7.PubMedView ArticleGoogle Scholar
  249. Cooper PL, Wahlqvist ML, Simpson RW. Sucrose versus saccharin as an added sweetener in non-insulin-dependent diabetes: short- and medium-term metabolic effects. Diab Med. 1988;5:676–80.View ArticleGoogle Scholar
  250. Colagiuri S, Miller JJ, Edwards RA. Metabolic effects of adding sucrose and aspartame to the diet of subjects with noninsulin-dependent diabetes mellitus. Am J Clin Nutr. 1989;50:474–8.PubMedGoogle Scholar
  251. Kullessa Nehrling J, Kobe P, McLane MP. Aspartame use by persons with diabetes. Diabetes Care. 1985;8:415–7.PubMedView ArticleGoogle Scholar
  252. Mezitis NHE, Maggio CA, Koch P, Quddoos A, Allison DB, Pi-Sunyer FX. Glycemic effect of a single high oral dose of the novel sweetener sucralose in patients with diabetes. Diabetes Care. 1996;19:1004–5.PubMedView ArticleGoogle Scholar
  253. Temizkan S, Deyneli O, Gunes M, Yasar M, Yazici D, Imeryuz N, Haklar G, Sirikci O, Yavuz D. Effect of artificial sweeteners on blood glucose, GLP-1, PYY, insulin and c-peptide levels in patients with type 2 diabetes. http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2013.DGM.15.SAT-831.
  254. Argyri K, Sotiropoulos A, Psarou E, Papazafiropoulou A, Zampelas A, Kapsokefalou M. Dessert formulation using sucralose and dextrin affects favorably postprandial response to glucose, insulin, and C-peptide in type 2 diabetic patients. Rev Diabet Stud. 2013;10:39–48.PubMedPubMed CentralView ArticleGoogle Scholar
  255. Okuno G, Kawakami F, Tako H. Glucose tolerance, blood lipid, insulin and glucagon concentration after single or continuous administration of aspartame in diabetics. Diabetes Res Clin Pract. 1986;2:23–7.PubMedView ArticleGoogle Scholar
  256. Pröls H, Wittmann P, Haslbeck M, Mehnert H. Investigations on the effect of high sodium cyclamate doses on the metabolism of diabetics. Munch Med Wochenschr. 1974;116:1885–8.Google Scholar
  257. Shigeta H, Yoshida T, Nakai M, Mori H, Kano Y, Nishioka H, Kajiyama S, Kitagawa Y, Kanatsuna T. Kondo M, et al. Effects of aspartame on diabetic rats and diabetic patients. 1985;31:533–40.Google Scholar
  258. Barriocanal LA, Palacios M, Benitez G, Benitez S, Jimenez JT, Jimenez N, Rojas V. Apparent lack of pharmacological effect of steviol glycosides used as sweeteners in humans. A pilot study of repeated exposures in some normotensive and hypotensive individuals and in type 1 and type 2 diabetics. Regul Toxicol Pharmacol. 2008;51:37–41.PubMedView ArticleGoogle Scholar
  259. Maki KC, Curry LL, McKenney JM, Farmer MV, Reeves MS, Dicklin MR. Glycemic and blood pressure responses to acute doses of rebaudioside a, a steviol glycoside, in subjects with normal glucose tolerance or type 2 diabetes mellitus. FASEB J. 2009;23Google Scholar
  260. Gregersen S, Jeppesen PB, Holst JJ, Hermansen K. Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metab Clin Exp. 2004;53:73–6.PubMedView ArticleGoogle Scholar
  261. Ritu M, Nandini J. Nutritional composition of Stevia Rebaudiana, a sweet herb, and its hypoglycaemic and hypolipidaemic effect on patients with non-insulin dependent diabetes mellitus. J Sci Food Agric. 2016;96:4231–4.PubMedView ArticleGoogle Scholar
  262. Kassi E, Landis G, Pavlaki A, Lambrou G, Mantzou E, Androulakis I, Giannakou A, Papanikolaou E, Chrousos GP. Acute effects of stevia rebaudiana extract on postprandial glucose metabolism in patients with metabolic syndrome. Endocr Rev. 2016;37Google Scholar
  263. Raben A, Vasilaras TH, Moller AC, Astrup A. Sucrose compared with artificial sweeteners: different effects on ad libitum food intake and body weight after 10 wk of supplementation in overweight subjects. In Clin Nutr. 76:721–92002. 721-9Google Scholar
  264. Chan P, Tomlinson B, Chen YJ, Liu JC, Hsieh MH, Cheng JT. A double-blind placebo-controlled study of the effectiveness and tolerability of oral stevioside in human hypertension. Br J Clin Pharmacol. 2000;50:215–20.PubMedPubMed CentralView ArticleGoogle Scholar
  265. Tate DF, Turner-McGrievy G, Lyons E, Stevens J, Erickson K, Polzien K, Diamond M, Wang X, Popkin B. Replacing caloric beverages with water or diet beverages for weight loss in adults: main results of the choose healthy options consciously everyday (CHOICE) randomized clinical trial.[erratum appears in am J Clin Nutr. 2013 Dec;98(6):1599]. Am J Clin Nutr. 2012;95:555–63.PubMedPubMed CentralView ArticleGoogle Scholar
  266. Memon M, MacDonald I, Bennett T. Effect of mental stress on cardiovascular function at rest and after ingestion of fructose or sucralose in healthy, white European males. Turk J Med Sci. 2013;43:913–8.View ArticleGoogle Scholar
  267. Ferri LAF, Alves-Do-Prado W, Yamada SS, Gazola S, Batista MR, Bazotte RB. Investigation of the antihypertensive effect of oral crude stevioside in patients with mild essential hypertension. Phytoter Res. 2006;20:732–6.View ArticleGoogle Scholar
  268. Chen L, Caballero B, Mitchell DC, Loria C, Lin PH, Champagne CM, Elmer PJ, Ard JD, Batch BC, Anderson CA, Appel LJ. Reducing consumption of sugar-sweetened beverages is associated with reduced blood pressure: a prospective study among United States adults.[Erratum appears in Circulation. 2010 Jul 27;122(4):e408]. Circulation. 2010;121:2398–406.Google Scholar
  269. Duffey KJ, Steffen LM, Van Horn L, Jacobs DR, Popkin BM. Dietary patterns matter: diet beverages and cardiometabolic risks in the longitudinal coronary artery risk development in young adults (CARDIA) study. Am J Clin Nutr. 2012;95:909–15.PubMedPubMed CentralView ArticleGoogle Scholar
  270. Fung TT, Malik V, Rexrode KM, Manson JE, Willett WC, Hu FB. Sweetened beverage consumption and risk of coronary heart disease in women. Am J Clin Nutr. 2009;89:1037–42.PubMedPubMed CentralView ArticleGoogle Scholar
  271. Winkelmayer WC, Stampfer MJ, Willett WC, Curhan GC. Habitual caffeine intake and the risk of hypertension in women. JAMA. 2005;294:2330–5.PubMedView ArticleGoogle Scholar
  272. Buss NE, Renwick AG, Donaldson KM, George CF. The metabolism of cyclamate to cyclohexylamine and its cardiovascular consequences in human volunteers. Toxicol Appl Pharmacol. 1992;115:199–210.PubMedView ArticleGoogle Scholar
  273. Fernandes J, Arts J, Dimond E, Hirshberg S, Lofgren IE. Dietary factors are associated with coronary heart disease risk factors in college students. Nutr Res. 2013;33:647–52.PubMedView ArticleGoogle Scholar
  274. Bernardo WM, Simoes RS, Buzzini RF, Nunes VM, Glina F. Adverse effects of the consumption of artificial sweeteners - systematic review. Rev Assoc Med Bras. 2016;62:120–2.PubMedView ArticleGoogle Scholar
  275. Borkum JM. Migraine triggers and oxidative stress: a narrative review and synthesis. Headache. 2016;56:12–35.PubMedView ArticleGoogle Scholar
  276. Hendriksen MA, Tijhuis MJ, Fransen HP, Verhagen H, Hoekstra J. Impact of substituting added sugar in carbonated soft drinks by intense sweeteners in young adults in the Netherlands: example of a benefit-risk approach. Eur J Nutr. 2011;50:41–51.PubMedView ArticleGoogle Scholar
  277. Pereira MA. Diet beverages and the risk of obesity, diabetes, and cardiovascular disease: a review of the evidence. Nutr Rev. 2013;71:433–40.PubMedView ArticleGoogle Scholar
  278. Russell WR, Baka A, Bjorck I, Delzenne N, Gao D, Griffiths HR, Hadjilucas E, Juvonen K, Lahtinen S, Lansink M, et al. Impact of diet composition on blood glucose regulation. Crit Rev Food Sci Nutr. 2016;56:541–90.PubMedView ArticleGoogle Scholar
  279. Shankar P, Ahuja S, Sriram K. Non-nutritive sweeteners: review and update. Nutrition (Burbank, Los Angeles County, Calif). 2013;29:1293–9.View ArticleGoogle Scholar
  280. Spencer M, Gupta A, Dam LV, Shannon C, Menees S, Chey WD. Artificial sweeteners: a systematic review and primer for gastroenterologists. J Neurogastroenterol Motil. 2016;22:168–80.PubMedPubMed CentralView ArticleGoogle Scholar
  281. Timpe Behnen EM, Ferguson MC, Carlson A. Do sugar substitutes have any impact on glycemic control in patients with diabetes? J Pharm Technol. 2013;29:61–5.View ArticleGoogle Scholar
  282. Poolsup N, Pongmesa T, Cheunchom C, Rachawat P, Boonsong R. Meta-analysis of the efficacy and safety of stevioside (from stevia rebaudiana bertoni) in blood pressure control in patients with hypertension. In Value in Health. 15:A6302012:A630.Google Scholar
  283. Urban JD, Carakostas MC, Taylor SL. Steviol glycoside safety: are highly purified steviol glycoside sweeteners food allergens? Food Chem Toxicol. 2015;75:71–8.PubMedView ArticleGoogle Scholar
  284. Wang DD, Shams-White M, Bright OJ, Parrott JS, Chung M. Creating a literature database of low-calorie sweeteners and health studies: evidence mapping. BMC Med Res Methodol. 2016;16:1.PubMedPubMed CentralView ArticleGoogle Scholar
  285. Palmer JR, Boggs DA, Krishnan S, Hu FB, Singer M, Rosenberg L. Sugar-sweetened beverages and incidence of type 2 diabetes mellitus in African American women. Arch Int Med. 2008;168:1487–92.View ArticleGoogle Scholar
  286. Sakurai M, Nakamura K, Miura K, Takamura T, Yoshita K, Nagasawa S, Morikawa Y, Ishizaki M, Kido T, Naruse Y, et al. Sugar-sweetened beverage and diet soda consumption and the 7-year risk for type 2 diabetes mellitus in middle-aged Japanese men. Eur J Nutr. 2014;53:251–8.PubMedView ArticleGoogle Scholar
  287. Grenby TH. Dental plaque, dental caries and sugar intake. The effects on the plaque of a low-calorie sweetener used in beverages in place of ordinary sugar. Brit Dent J. 1975;139:129–34.PubMedView ArticleGoogle Scholar
  288. Serra Majem L, Garcia Closas R, Ramon JM, Manau C, Cuenca E, Krasse B. Dietary habits and dental caries in a population of Spanish schoolchildren with low levels of caries experience. Caries Res. 1993;27:488–94.PubMedView ArticleGoogle Scholar
  289. Serra-Majem L, Bassas L, Garcia-Glosas R, Ribas L, Ingles C, Casals I, Saavedra P, Renwick AG. Cyclamate intake and cyclohexylamine excretion are not related to male fertility in humans. Food Addit Contam. 2003;20:1097–104.PubMedView ArticleGoogle Scholar
  290. Petersen SB, Rasmussen MA, Olsen SF, Vestergaard P, Molgaard C, Halldorsson TI, Strom M. Maternal dietary patterns during pregnancy in relation to offspring forearm fractures: prospective study from the Danish National Birth Cohort. Nutrients. 2015;7:2382–400.PubMedPubMed CentralView ArticleGoogle Scholar
  291. Samant SS, Wilkes K, Odek Z, Seo HS. Tea-induced calmness: sugar-sweetened tea calms consumers exposed to acute stressor. Sci Rep. 2016;6:36537.PubMedPubMed CentralView ArticleGoogle Scholar
  292. Thakkar P, Arora K, Goyal K, Das RR, Javadekar B, Aiyer S, Panigrahi SK. To evaluate and compare the efficacy of combined sucrose and non-nutritive sucking for analgesia in newborns undergoing minor painful procedure: a randomized controlled trial. J Perinatol. 2016;36:67–70.PubMedView ArticleGoogle Scholar
  293. Paganini-Hill A, Kawas CH, Corrada MM. Non-alcoholic beverage and caffeine consumption and mortality: the leisure world cohort study. Prev Med. 2007;44:305–10.PubMedView ArticleGoogle Scholar

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