Introduction
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 |
Objectives
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Identify all potential health outcomes associated with regular NNS consumption;
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Define the number and types of primary studies (i.e. studies that collect original data from subjects) available for each health outcome;
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Identify any gaps in the evidence base for the health outcomes of regular NNS consumption.
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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
Inclusion criteria
Search strategy
Data extraction and management
Results
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 |
Health outcomes assessed in the included studies
Short-term outcomes
Appetite and short term food intake
Long-term health outcomes in healthy populations
Cancer
Chronic kidney disease
Dental health (caries)
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 |
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 | ↑ |