A systematic review on the effect of sweeteners on glycemic response and clinically relevant outcomes

  • Natasha Wiebe1,

    Affiliated with

    • Raj Padwal1,

      Affiliated with

      • Catherine Field2,

        Affiliated with

        • Seth Marks3,

          Affiliated with

          • Rene Jacobs2 and

            Affiliated with

            • Marcello Tonelli1Email author

              Affiliated with

              BMC Medicine20119:123

              DOI: 10.1186/1741-7015-9-123

              Received: 14 June 2011

              Accepted: 17 November 2011

              Published: 17 November 2011

              Abstract

              Background

              The major metabolic complications of obesity and type 2 diabetes may be prevented and managed with dietary modification. The use of sweeteners that provide little or no calories may help to achieve this objective.

              Methods

              We did a systematic review and network meta-analysis of the comparative effectiveness of sweetener additives using Bayesian techniques. MEDLINE, EMBASE, CENTRAL and CAB Global were searched to January 2011. Randomized trials comparing sweeteners in obese, diabetic, and healthy populations were selected. Outcomes of interest included weight change, energy intake, lipids, glycated hemoglobin, markers of insulin resistance and glycemic response. Evidence-based items potentially indicating risk of bias were assessed.

              Results

              Of 3,666 citations, we identified 53 eligible randomized controlled trials with 1,126 participants. In diabetic participants, fructose reduced 2-hour blood glucose concentrations by 4.81 mmol/L (95% CI 3.29, 6.34) compared to glucose. Two-hour blood glucose concentration data comparing hypocaloric sweeteners to sucrose or high fructose corn syrup were inconclusive. Based on two ≤10-week trials, we found that non-caloric sweeteners reduced energy intake compared to the sucrose groups by approximately 250-500 kcal/day (95% CI 153, 806). One trial found that participants in the non-caloric sweetener group had a decrease in body mass index compared to an increase in body mass index in the sucrose group (-0.40 vs 0.50 kg/m2, and -1.00 vs 1.60 kg/m2, respectively). No randomized controlled trials showed that high fructose corn syrup or fructose increased levels of cholesterol relative to other sweeteners.

              Conclusions

              Considering the public health importance of obesity and its consequences; the clearly relevant role of diet in the pathogenesis and maintenance of obesity; and the billions of dollars spent on non-caloric sweeteners, little high-quality clinical research has been done. Studies are needed to determine the role of hypocaloric sweeteners in a wider population health strategy to prevent, reduce and manage obesity and its consequences.

              Background

              Non-caloric sweeteners have been available commercially since the late 1800s [1] and their use in food products and as table-top sweeteners is increasing - perhaps due in part to aggressive marketing promoting their capacity to induce weight loss and weight maintenance [2, 3]. In 2007, non-caloric and/or high-intensity sweeteners accounted for 16% of the US sweetener market (approximately 0.5 billion USD [4]) and projected sales of these products are expected to exceed one billion USD by 2014 [5].

              Sugar alcohols can also be used as sweetener additives and provide less calories per gram than saccharides (sugars). However because sugar alcohols cause gastrointestinal symptoms in some individuals due to incomplete absorption in the small intestine, they may be used less frequently than saccharides. A variety of different saccharides is commonly used to sweeten foods, such as sucrose, fructose, glucose, maltose, isomaltulose, and fructooligosaccharide (FOS). FOS has half the calories per gram than sucrose, fructose, or glucose. Most recently, fructose (a highly commercially used sweetener used in combination with glucose as high fructose corn syrup (HFCS)) has been controversially linked with hypertriglyceridemia [6].

              The effects of different sweeteners on clinically relevant outcomes such as weight management, blood glucose and lipids have been incompletely studied. The main metabolic complications of obesity and type 2 diabetes may be prevented and managed in full or in part with dietary modification, including the use of sweeteners that provide little or no calories (hypocaloric sweeteners) [710].

              This review systematically summarizes the available randomized trial evidence to determine the comparative effectiveness of sweetener additives (non-caloric, sugar alcohols, and saccharides; Table 1) in food.
              Table 1

              Description of sweeteners

              Sweetener

              Commercial products

              Nutritive, kcal/g

              Sweetness intensity,

              relative to sucrose

              Non-caloric

              Acesulfame-K [8385]

              Sunett®

              0

              200

              Aspartame [8386]

              Equal®, NutraSweet®

              4

              180

              Cyclamate [8385]

              0

              30-50

              Saccharin [8385]

              Sweet'N Low®, Sugar Twin®, Hermesetas®

              0

              300-500

              Sucralose [8385]

              Splenda®a

              0

              600

              Sugar alcohol

              Hydrogenated starch hydrolysate (HSH) [85]

              ≤3

              0.4-0.9

              Lycasin [87]

              2.4

              0.75

              Maltitol [85]

              3

              0.9

              Sorbitol [85, 86]

              2.6

              0.6

              Saccharide

              Fructooligosaccharides (FOS) [88]

              2

              0.3-0.6

              Fructose [85, 86, 89]

              4

              1-2

              Glucose [86, 89]

              ≥ 4

              0.5-1

              High fructose corn syrup (HFCS) [85, 89]

              Varieties: HFCS 55, HFCS 42, HFCS 90

              ≥ 4

              ~1

              Honey [90]

              ≥ 4

              1-1.5

              Isomaltulose [88, 91]

              Palatinose

              4

              0.5

              Maltose [86, 89]

              ≥ 4

              0.5

              Sucromalt [88]

              4

              0.7

              Sucrose [86, 89]

              4

              1 (reference)

              Tagatose [83]

              1.5

              0.9

              Trehalose [92]

              4

              0.45

              aSplenda also contains maltodextrin and sometimes dextrose which are both nutritive

              Methods

              This systematic review was conducted and reported according to guidelines [11].

              Data sources and searches

              We did a comprehensive search designed by a MLIS-trained librarian to identify all randomized controlled trials (RCTs) comparing sweeteners in generally healthy, overweight/obese and/or diabetic participants. We included only trials published in English as full peer-reviewed manuscripts. MEDLINE (1950 to January 13, 2011), EMBASE (1980 to January 13, 2011), CENTRAL (January 13, 2011), and CAB (January 13, 2011) were searched. No existing systematic reviews were found. The specific strategies used are provided in Additional File 1. The citations and abstracts were screened by two reviewers to identify pertinent trials. Any study considered potentially relevant by one or both reviewers was retrieved for further consideration.

              Study selection

              We considered non-caloric sweeteners to include high-intensity caloric sweeteners that are functionally non-caloric simply due to extremely low doses (for example, aspartame). Each potentially relevant study was independently assessed by two reviewers for inclusion in the review using predetermined eligibility criteria. Disagreements were resolved by consultation with a third party. Trials with healthy, overweight/obese, and/or diabetic adult (≥ 16 years old) participants meeting the following criteria were eligible for inclusion: parallel or crossover RCTs; weight change, energy intake, lipids, glycated hemoglobin (HbA1C), or insulin resistance were reported; had at least two groups comparing different sweeteners (for example, glucose, fructose, sucrose, other saccharides, sugar alcohols, non-caloric sweeteners: aspartame, saccharin, stevioside, sucralose); and where follow-up was at least one week in duration (see the Box in Additional File 1 for study selection summary). RCTs measuring 2-hour blood (serum or plasma) glucose responses in similar populations without the follow-up requirement were also reviewed. All outcomes selected for study (including weight change) are reversible and thus (providing that order was randomly assigned), a cross-over design should be appropriate. Trials with less than ten participants per group were excluded to improve the efficiency of the work without an appreciable loss of power, and with the possible elimination of some small study bias. Trials aimed at evaluating exercise performance or memory enhancement were excluded. Trials with placebo controls were also excluded as we aimed to investigate comparative effectiveness of different sweeteners, as opposed to exploring the implications of avoiding sweeteners altogether.

              Data extraction and quality assessment

              A standardized data extraction method was performed by a single reviewer. A second reviewer checked the extracted data for accuracy. The following properties of each trial were recorded in a database: trial characteristics (country, design, sample size, duration of follow-up); participants (age, gender, co-morbidity (obesity, diabetes mellitus - type 1 and 2), baseline body mass index (BMI), diabetic therapy (insulin, oral antihyperglycemic agents, diet, and so on); sweetener characteristics (type, quantity, schedule); diet (that is, daily caloric content by macronutrient/fiber content); and outcomes. Outcomes included weight change (absolute, BMI), energy intake, lipid measures (total cholesterol, triglycerides, high density lipoprotein (HDL), low density lipoprotein (LDL)), HbA1C, insulin resistance (for example, Homeostatic Model Assessment (HOMA) index), and 2-hour blood glucose (with or without meals).

              Risk of bias was assessed using items known to be associated with the magnitude of results (that is, method of randomization, double-blinding, description of withdrawals/dropouts, and allocation concealment) [12, 13]. Source of funding was also extracted given its potential to introduce bias [14].

              Data synthesis and analysis

              Data were analyzed using Stata 11.1 (http://​www.​stata.​com). Missing standard deviations (SDs) were imputed using the maximum value reported in any included study [15]. Missing correlations for change from baseline and for differences between crossover trial periods were assigned a value of 0.63, the maximum reported value in the included studies. Changes from baseline means were used in place of final means in parallel randomized trials. For weight change, the baseline value prior to the immediate period was used. The mean difference (MD) was used to summarize outcomes. Due to expected diversity between studies, we decided a priori to combine results using a random effects model (Stata command: metan). Additionally we planned to examine the association between certain variables (population, dose, diet, age, gender, and bias criteria) and the effect of specific sweeteners on outcomes, and publication bias with weighted regression [16], however the available comparisons were too sparse to pool trials with outcomes of one week or less. For 2-hour responses, we pooled comparisons by type of sweetener and ordered the matrix tables by expected order of efficacy [17] (that is, non-caloric sweeteners, sugar alcohols, other saccharides, fructose, sucrose, and glucose). Statistical heterogeneity was quantified using the τ2 statistic (between-study variance) [18]. Furthermore, we explored comparative effectiveness of sweeteners on 2-hour responses using network meta-analysis [19] (specifically, Markov chain Monte Carlo [MCMC] methods within a Bayesian framework) in WinBugs (http://​www.​mrc-bsu.​cam.​ac.​uk/​bugs; code was obtained from Ades et al. [20]). Network analysis extends meta-analysis from simply pooling directly compared treatments (direct evidence) to pooling data from studies not directly compared but linked via one or more common comparators (indirect evidence) by assuming consistency of the evidence [19]. Therefore, this technique facilitates the comparison of any two sweeteners not directly compared in any one study. We used non-informative prior distributions: uniform for the between-study variance (range 0 to 20) and Gaussian for the other parameters (mean 0 and variance 10,000). All chains were run for 10,000 iterations after 1,000 burn-in iterations. Convergence of the MCMC algorithm was assessed using autocorrelation plots. By-population results were generated. Inconsistency in the network (disagreement between direct and mixed evidence) was measured using back-calculations [21]. Ninety-five present Bayesian credible intervals are reported.

              Results

              Quantity of research available

              The searches identified 3,666 unique records with no trials found outside the main literature searches. After initial screening, 491 articles were retrieved for detailed evaluation (Figure 1) and of these 440 articles were excluded resulting in 53 trials (from 51 publications) that met the selection criteria. Disagreements about the inclusion of studies occurred in 11% of the articles (kappa = 0.71). Fourteen were ultimately included. The remaining were excluded for the following reasons: thirteen with no relevant control group, nine with no relevant population, five with no relevant intervention group, four due to study design, four for small sample size, and one for no usable data. The sweeteners studied in eligible trials are described in Table 1.
              http://static-content.springer.com/image/art%3A10.1186%2F1741-7015-9-123/MediaObjects/12916_2011_487_Fig1_HTML.jpg
              Figure 1

              Flow diagram of trials considered for inclusion. This flow diagram depicts each step in the process of trial selection.

              Characteristics of 2-hour response trials

              Of the forty included trials with 2-hour response data (703 participants; Table 2), three trials compared a non-caloric sweetener (aspartame [22, 23], or sucralose [24]) to a saccharide (fructose [24] or sucrose [22, 23]); one trial compared a non-caloric to another non-caloric (aspartame versus saccharin [25]); four trials compared a sugar alcohol or a malt containing a sugar alcohol (sorbitol [26], xylitol [26, 27], maltitol [26], Lycasin [26, 28], or a hydrogenated starch hydrolysate (HSH) [29]) to a saccharide (glucose [26, 28, 29] or sucrose [27]); and thirty-two trials compared a saccharide to another saccharide (glucose [3051], fructose [3134, 36, 3841, 4447, 49, 50], mixtures of glucose and fructose [that is, sucrose [34, 37, 39, 42, 43, 4857], HFCS [42, 54, 55, 58], honey [48, 57, 59], glucose/fructose equivalent honey [59]], isomaltulose [52, 56], maltose [53], sucromalt [58], trehalose [30], or a mixture of trehalose and fructose [30]). Approximately half of the doses for saccharides were less than the 60 g/day recommended for diabetic patients on a 2,000 kcal diet; the remainder exceeded 60 g/day (typically 75 g). All of the doses for sugar alcohols exceeded the 10 g/day recommendation (range 20 to 50 g), which is aimed at limiting gastrointestinal symptoms. None of the four non-caloric sweetener groups were above Acceptable Daily Intake (ADI) values.
              Table 2

              Description of included 2-hour response randomized trials

              Author,

              Year,

              Country

              Population,

              Mean BMI (kg/m2)

              Sweetener 1:

              Type,

              Quantity

              Sweetener 2:

              Type,

              Quantity

              Medium

              Study design,

              Follow-up,

              Sample size

              Mean age (y),

              % female

              Allocation concealment,

              Jadad score,

              Funding

              Non-caloric vs Saccharide

              Gonzalez-Ortiz [24]

              2009

              Mexico

              General

              23

              Sucralose (Enterex Diabetic®)

              45% once

              Mixtureb

              (Glucerna SR®)

              50% once

              Drink

              xRCT

              2 1d periods

              (3d wo)

              14

              22

              64

              Unclear

              2

              -

              Prat-Larquemin [22]

              2000

              France

              General

              20

              Aspartame

              0.27 g once

              Sucrose

              90 g once

              Cheese

              xRCT

              2 1d periods

              (1wk wo)

              24

              23

              0

              Unclear

              3

              Mixede

              Melchior [23]

              1991

              France

              General

              21

              Aspartame

              80mg once

              Sucrose

              50 g once

              Drink

              xRCT

              2 1d periods

              10

              22

              70

              Unclear

              1

              Public

              Non-caloric vs Non-caloric

              Horwitz [25]

              1988

              US

              55% General/45% DM2

              < 25

              Aspartame

              400 mg once

              Saccharin

              135 mg once

              Unsweetened drink

              xRCT

              2 1d periods

              (1wk wo)

              22

              41

              77

              Unclear

              1

              Private

              Sugar Alcohol vs Saccharide

              Rizkalla [28]

              2002

              France

              50% General

              25

              50% DM2

              27

              Lycasin

              50 g once

              Glucose

              50 g once

              None

              xRCT

              2 1d periods

              (1wk wo)

              12

              40

              0

              Unclear

              2

              Private

              Nguyen [26]

              1993

              France

              General

              -

              Lycasin

              20 g once

              Sorbitol

              20 g once

              Xylitol

              20 g once

              Maltitol

              20 g once

              Glucose

              20 g once

              None

              xRCT

              5 1d periods

              (1wk wo)

              10

              33

              50

              Unclear

              1

              Private

              Wheeler [29]

              1990

              US

              33% General

              24f

              33% DM2

              32

              33% DM1

              23

              HSH6075

              50 g once

              HSH5875

              50 g once

              Glucose

              50 g once

              None

              xRCT

              3 1d periods

              18

              47

              50

              Unclear

              2

              Mixed

              Hassinger [27]

              1981

              Germany

              DM1

              -

              Xylitol

              30 g once

              Sucrose

              30 g once

              Meal

              xRCT

              2 1d periods

              14

              29

              -

              Unclear

              1

              Private

              Saccharide vs Saccharide

              Maki [30]

              2009

              US

              Obese

              35

              Trehalose

              75 g once

              Trehalose/Fructose

              75 g once

              Glucose

              75 g once

              None

              xRCT

              3 1d periods

              21

              50

              0

              Unclear

              3

              Private

              Teff [31]

              2009

              US

              Obese

              35

              Fructose

              30%

              Glucose

              30%

              Meals & Drinks

              xRCT

              2 2d periods

              (1mo wo)

              17

              33

              47

              Unclear

              1

              Public

              Van Can [52]

              2009

              Netherlands

              Overweight

              28

              Isomaltulose

              75 g once

              Sucrose

              75 g once

              None

              xRCT

              2 1d periods

              (1wk wo)

              10

              31

              20

              Unclear

              1

              Private

              Grysman [58] A

              2008

              Canada

              General

              24

              Sucromalt

              50 g once

              HFCS42

              50 g once

              None

              xRCT

              2 1d periods

              10

              28

              30

              Unclear

              2

              Private

              Grysman [58] B

              2008

              Canada

              General

              24

              Sucromalt

              80 g once

              HFCS42

              80 g once

              None

              xRCT

              2 1d periods

              10

              25

              50

              Unclear

              2

              Private

              Grysman [58] C

              2008

              Canada

              General

              24

              Sucromalt

              50 g once

              HFCS42

              50 g once

              Glucose

              50 g once

              Meal

              xRCT

              3 1d periods

              20

              37

              60

              Unclear

              2

              Private

              Munstedt [59]

              2008

              Germany

              General

              23

              Glucose/Fructosea

              155 g once

              Honey

              221 g once

              None

              xRCT

              2 1d periods (1wk wo)

              10

              28

              0

              Unclear

              2

              -

              Stanhope [54]

              2008

              US

              General

              25

              HFCS55

              25% thrice

              Sucrose

              25% thrice

              3 Meals

              xRCT

              2 1d periods (1mo wo)

              34

              35

              47

              Unclear

              1

              Mixed

              Bowen [32]

              2007

              Australia

              Overweight/

              Obese

              33

              Fructose

              50 g once

              Glucose

              50 g once

              Drink

              xRCT

              2 1d periods

              (7d wo)

              28

              57

              0

              Unclear

              4

              Mixed

              Chong [33]

              2007

              UK

              General

              25

              Fructose

              0.75 g/kg once

              Glucose

              0.75 g/kg once

              Drink

              xRCT

              2 1d periods

              (6wk wo)

              14

              43

              43

              Unclear

              1

              Mixed

              Melanson [55]

              2007

              US

              General

              22

              HFCS55

              30% TID

              Sucrose

              30% TID

              3 Meals

              xRCT

              2 2d periods

              (6wk wo)

              30

              33

              100

              Unclear

              2

              Private

              Visvanathan [34]

              2005

              Australia

              General

              26

              Sucrose

              50 g once

              Fructose

              50 g once

              Glucose

              50 g once

              None

              xRCT

              3 1d periods

              (3d wo)

              10

              72

              60

              Unclear

              1

              Public

              Teff [35]

              2004

              US

              General

              23

              Fructose

              30% TID

              Glucose

              30% TID

              3 Meals

              xRCT

              2 2d periods

              (1mo wo)

              12

              25

              100

              Unclear

              1

              Mixed

              Qin [53]

              2003

              Japan

              General

              23

              Maltose

              75 g QIDx4h

              Sucrose

              75 g QIDx4h

              None

              xRCT

              2 1d periods

              (1wk wo)

              10

              22

              0

              Unclear

              1

              -

              Vozzo [36]

              2002

              Australia

              50% IGT/50% DM2

              31

              Fructose

              75 g once

              Glucose

              75 g once

              None

              xRCT

              2 1d periods

              (5d wo)

              20

              56

              40

              Unclear

              1

              Mixed

              Spiller [37]

              1998

              US

              General

              -

              Sucrose

              90 g once

              Glucose

              90 g once

              None

              xRCT

              2 1d periods

              (1wk wo)

              10

              29

              50

              Unclear

              1

              Private

              Stewart [38]

              1997

              Canada

              General

              20-27

              Fructose

              30 g SID

              Glucose

              33.5 g SID

              Meal

              xRCT

              2 1d periods

              13

              25

              0

              Unclear

              1

              Private

              Blaak [39]

              1996

              Netherlands

              General

              -

              Sucrose

              75 g once

              Fructose

              75 g once

              Glucose

              75 g once

              None

              xRCT

              3 1d periods

              (1wk wo)

              10

              28

              0

              Unclear

              1

              Mixed

              Fukagawa [40]

              1995

              US

              General

              -

              Fructose

              75 g onced

              Glucose

              75 g once

              None

              xRCT

              2 1d periods

              16

              47

              38

              Unclear

              1

              Public

              Schwarz [41]

              1992

              Switzerland

              43% General

              21

              57% Overweight

              30

              Fructose

              75 g once

              Glucose

              75 g once

              Meal

              xRCT

              2 1d periods

              (4d wo)

              23

              25

              100

              Unclear

              1

              Mixed

              Bukar [42]

              1990

              US

              DM2

              -

              HFCS

              27 g (12.2 g Fructose/14.8 g Glucose) once

              Sucrose

              33.5 g once

              Glucose

              50 g once

              HFCS: Tofu frozen dessert

              Sucrose: Ice cream

              Glucose: None

              xRCT

              3 1d periods

              (2d wo)

              12

              51

              50

              Unclear

              1

              -

              Georgakopoulos [43]

              1990

              Greece

              General

              -

              Sucrose

              20 g once

              Glucose

              20 g once

              None

              xRCT

              2 1d periods

              (3d wo)

              17

              Range 25-40

              29

              Unclear

              1

              -

              Kawai [56]

              1989

              Japan

              50% General

              20

              50% DM2

              23

              Isomaltulose

              50 g once

              Sucrose

              50 g once

              None

              xRCT

              2 1d periods

              (2d wo)

              20

              39

              30

              Unclear

              1

              Mixed

              Schwarz [44]

              1989

              Switzerland

              General

              21

              Fructose

              75 g once

              Glucose

              75 g once

              Drink

              xRCT

              2 1d periods

              (4d wo)

              20

              23

              50

              Unclear

              1

              Private

              Simonson [45]

              1988

              Switzerland

              DM2/General/Obesef

              -

              Fructose

              75 g once

              Glucose

              75 g once

              None

              xRCT

              2 1d periods

              (1wk wo)

              37

              53

              51

              Unclear

              1

              Mixed

              Jansen [46]

              1987

              Netherlands

              General

              -

              Fructose

              75 g once

              Glucose

              75 g once

              None

              xRCT

              2 1d periods

              (1wk wo)

              20

              52

              50

              Unclear

              1

              Public

              Tappy [47]

              1986

              Switzerland

              General

              -

              Fructose

              75 g once

              Glucose

              75 g once

              None

              xRCT

              2 1d periods

              (2d wo)

              10

              27c

              65c

              Unclear

              1

              Mixed

              Erkelens [57]

              1985

              Netherlands

              33% Generalf/33% DM2/17% DM1/17% insulin infusion DM1

              -

              Honey

              (22% Glucose/26% Fructose) SID

              Sucrose

              49% SID

              White bread & Cheese

              xRCT

              2 1d periods

              (2d wo)

              24

              47

              46

              Unclear

              1

              Mixed

              Samanta [48]

              1985

              UK

              46% General/31% DM1/23% DM2

              -

              Honey

              26 g once

              Sucrose

              26 g once

              Glucose

              26 g once

              None

              xRCT

              3 1d periods

              26

              40

              -

              Unclear

              1

              -

              Bantle [49]

              1983

              US

              31% General/38% DM1/31% DM2

              -

              Sucrose

              42 g once

              Fructose

              42 g once

              Glucose

              42 g once

              Meal

              xRCT

              3 1d periods

              32

              41

              56

              Unclear

              2

              Mixed

              Crapo [50]

              1982

              US

              38% General/23% IGTf/38% DM2

              -

              Sucrose

              63 g once

              Sucrose

              52 g once

              Fructose

              63 g once

              Fructose

              52 g once

              Glucose

              69.9 g once

              Sucrose & Fructose 63 g: cake

              Sucrose & Fructose 52 g: ice cream

              None

              xRCT

              5 1d periods

              (1d wo)

              26

              43

              42

              Unclear

              1

              Mixed

              Mann [51]

              1971

              South Africa

              General

              -

              Sucrose

              60 g once

              Glucose

              60 g once

              Meal

              xRCT

              2 1d periods

              (2d wo)

              19

              Range 20-58

              0

              Unclear

              1

              Public

              DM1, type 1 diabetes mellitus; DM2, type 2 diabetes mellitus; IGT, impaired glucose tolerance; UK, United Kingdom; US, United States; HFCS, high fructose corn syrup; FOS, fructooligosaccharide; SID, once a day; BID, twice a day; TID, three times a day; QID, four times a day; carb, carbohydrate; xRCT, randomized crossover trial; RCT, parallel randomized controlled trial; wo, washout; max, maximum "-" means the value was not reported in the study, and not described

              a'comparable Honey'

              bcontains isomaltulose, fructose, Sucromalt® (sucrose, maltose), and FOS

              capproximate because it includes 7 people from other studies written up in the same article

              dfactorial trial including 300 mg caffeine or 300 mg vitamin C

              eboth public and private sources of funding

              fgroup of participants dropped due to low group sample size

              Twelve trials included diabetic populations (range mean BMI 23 to 32 kg/m2) [25, 2729, 36, 42, 45, 4850, 56, 57], five trials exclusively studied overweight or obese individuals (range mean BMI 28 to 35 kg/m2) [30, 31, 41, 45, 52], and thirty-five trials included generally healthy individuals (range mean BMI 20 to 26 kg/m2). Median mean age was 35 years (range 22 to 72 years) and median sex distribution was 47% women.

              Sample size ranged from 10 to 37 (median 17), three studies (8%) had sample sizes ≥ 30 per group and all were randomized crossover trials. The median Jadad score was 1 (range 1 to 4); no studies reported concealing treatment allocation.

              2-hour blood glucose response

              Table 3 reports the results of the direct meta-analysis for all populations in the lower triangle and the mixed evidence from the Bayesian network (Figure 2) in the upper triangle. The network included 36 trials and 610 participants. The direct evidence from all nine comparisons was consistent with the mixed evidence from the network. There was large heterogeneity between trials (I2's ≥ 77%) for three of seven multi-study direct evidence comparisons. Two of the heterogeneous comparisons included a variety of sweeteners (that is, multiple sugar alcohols (τ2 = 9.05 (95% CI 2.94,32)), or multiple other sugars (τ2 = 1.72 (0.37,1.48))) within one category. In the fructose versus glucose comparison, six trials were responsible for the heterogeneity (τ2 = 1.40 (0.68,1.50)). Three [36, 45, 50] were subgroups of diabetic participants; they increased the magnitude of the mean difference. The other three trials [32, 33, 46] showed important differences prior to the 2-hour time point (data not shown) but at two hours showed little or no difference between sweeteners. The single estimate of heterogeneity (τ2) for the network meta-analysis was 0.65 (95% CI 0.35,1.10).
              Table 3

              Mean difference in serum glucose (mmol/L) at 2 hours post-sweetener consumption and overnight fast in all participants

              Non-

              caloric

              0.05

              0.98

              (-1.24,3.25)

              τ2 =0.65 (0.35,1.10)

              0.16

              (-1.46,1.80)

              consistent

              1.19

              (-0.56,2.94)

              0.07

              (-1.45,1.61)

              consistent

              -0.37

              (-2.07,1.29)

              -

              Sugar

              alcohols

              0.38

              -0.83

              (-2.66,1.03)

              0.21

              (-1.47,1.84)

              -0.93

              (-2.56,0.70)

              consistent

              -1.37

              (-2.96,0.18)

              consistent

              -0.40

              (-0.79,-0.01)

              N = 1

              -

              Other

              sugars

              0.01

              1.03

              (-0.13,2.20)

              -0.09

              (-1.00,0.81)

              consistent

              -0.55

              (-1.61,0.50)

              consistent

              -

              -

              -

              Fructose

              0.55

              -1.12

              (-1.95,-0.27)

              consistent

              -1.56

              (-2.18,-1.02)

              consistent

              0.30

              (-1.99,2.58)

              N = 2 I2 = 0

              τ2 = 0

              0.41

              (-2.44,3.26)

              N = 1

              -0.28

              (-1.67,1.11)

              N = 7 I2 = 84

              τ2 = 1.72

              (0.37,1.48)

              -0.41

              (-1.30,0.47)

              N = 9 I2 = 11

              τ2 = 0.17

              (0.58,2.41)

              Sucrose/

              HFCS/

              Honey

              0

              -0.45

              (-1.15,0.21)

              consistent

              -

              -2.20

              (-10.46,6.05)

              N = 3 I2 = 85

              τ2 = 9.05

              (2.94,32.22)

              0.10

              (-2.46,2.66)

              N = 2 I2 = 0

              τ2 = 0

              -1.40

              (-2.05,-0.74)

              N = 23 I2 = 77

              τ2 = 1.4 (0.68,1.50)

              -0.31

              (-0.53,-0.08)

              N = 15 I2 = 0

              τ2 = 0

              (0,0.28)

              Glucose

              0

              HFCS, high fructose corn syrup

              The mixed evidence of the Bayesian network analysis are in the upper triangle and the direct evidence calculated using the REML estimate of τ2 are in the lower triangle. Sweeteners are reported in the expected order of efficacy[17] (with the exception of other sugars) from the expected lowest to highest 2-hour glucose response, with the estimated probability (or rank) listed in the diagonal. Each table cell contains the mean difference (MD) with the accompanying 95% confidence intervals. In the cells with direct evidence, we also list the number of studies, the I2 (percent of heterogeneity due to between-study heterogeneity) and τ2 (the between-study variance). Blank cells in the lower triangle indicate that no direct evidence was available. In the cells with mixed evidence, we list whether the mixed evidence was consistent with the available direct evidence. Also, in the first cell of the mixed evidence, we list the single τ2 estimate for the mixed evidence. Results are the MD of the expected higher-ranked sweeteners compared to the expected lower-ranked sweeteners (for example, MD of sugar alcohols versus sucrose is 0.41 and is in column 2, row 5 for the direct results, and is -0.93 and is in column 5, row 2 for the network analysis results). MDs less than zero favor the expected higher-ranked sweetener (smaller glucose response). For example, sugar alcohols show an increased serum glucose response by 0.41 mmol/L compared to sucrose using the direct evidence. However, sugar alcohols show a decreased serum glucose response by 0.93 mmol/L using the mixed evidence. However, since both confidence intervals include zero, neither analysis allows a confident judgment about which sweetener is preferable. Pooled evidence significant at P < 0.05 are presented in bold font. All nine mixed and direct results are consistent.

              http://static-content.springer.com/image/art%3A10.1186%2F1741-7015-9-123/MediaObjects/12916_2011_487_Fig2_HTML.jpg
              Figure 2

              Network: blood glucose (mmol/L) at 2 hours post-sweetener consumption and overnight fast. HFCS, high fructose corn syrup. *non-caloric sweetener groups were unavailable in the network with diabetic participants.

              Reporting the mixed evidence, two comparisons: fructose versus sucrose (MD -1.12 mmol/L (-1.95,-0.27)), and fructose versus glucose (-1.56 mmol/L (-2.18,-1.02)) were statistically significant, all favoring fructose, but neither of the confidence limits excluded the possibility of non-clinically relevant differences (< 1·15 mmol/L - calculation based on a clinical important difference of 1% for HbA1C) [60]. The weighted regression test for publication bias was not significant.

              In the subnetwork of 31 trials enrolling participants without diabetes (446 participants; τ2 = 3.66 (1.66,7.31); Appendix Table 1 in Additional File 1), the direct evidence from all 8 comparisons was consistent with the mixed evidence from the network. The heterogeneity although reduced remained large between trials (I2's ≥ 60%) in both of the remaining multi-study direct evidence comparisons. Using the mixed evidence, three comparisons: fructose versus sucrose (-0.54 mmol/L (-1.06,-0.03)), fructose versus glucose (-0.89 mmol/L (-1.21,-0.59)), and fructose versus other sugars (-0.85 mmol/L (-1.47,-0.21)) were statistically significant, all favoring fructose, but none of the confidence limits excluded the possibility of non-clinically relevant differences.

              In the subnetwork of ten trials enrolling participants with diabetes (152 participants; Appendix Table 2 in Additional File 1), the direct evidence from all six comparisons was consistent with the mixed evidence from the network. Note, this network did not include non-caloric sweeteners. Because the estimate of τ2 (224 (0.14,139)) did not converge, we report our findings from the direct evidence. Three direct comparisons were significant and found clinically relevant differences between agents over the entire confidence interval span: fructose versus glucose in 5 trials with 52 participants (-4·81 mmol/L (-6·34,-3·29), I2 = 0%, τ2 = 0 (0,7.47)), HSH versus glucose in 1 trial [29] with 12 participants (-6·19 mmol/L (-9·78,-2·60)) and isomaltulose versus sucrose in 1 trial [52] with 20 participants (-3·44 mmol/L (-5·31,-1·56)).

              Characteristics of trials studying effects on weight management, blood glucose and blood lipids

              Of the 13 trials (412 participants; Table 4), 3 trials compared a non-caloric sweetener (aspartame [61], cyclamate [62], or a mixture [63]) to sucrose, and 10 trials compared a saccharide to a different saccharide (glucose [6466], fructose [64, 65, 67], mixtures of glucose and fructose [that is, sucrose [6672] or honey [69]], FOS [7173], a mixture of isomaltulose and sucrose [68], or tagatose [70]). No trials evaluated stevioside. Seven trials did not give any daily diet recommendations; one FOS trial recommended low-fiber intake [72]; one restricted added sweeteners to the assigned sweetener [62]; three trials restricted total energy levels and composition of macronutrients (55% carbohydrate, 30% fat, 15% protein) [64, 65, 67]; and another restricted total energy levels and the composition to the assigned sweetener plus calcium caseinate [66]. With three exceptions [63, 64, 66], the doses of sweeteners were at or below current clinical practice guideline (CPG) recommendations (10% of total energy intake (for example, 60 g of sucrose in a 2000 kcal diet) although only three trials [64, 65, 67] restricted overall energy intake, therefore further sweetener consumption may have exceeded current recommendations. One trial [63] prescribed sweeteners (simple carbohydrates) at 25% of total energy intake - the American Diabetes Association (ADA) 2004 recommended maximum. The earliest trial [66] prescribed sweeteners at 87% of total energy intake - they were differentiating energy availability from energy content.
              Table 4

              Characteristics of included randomized trials with effects on weight management, blood glucose and blood lipids

              Author,

              Year,

              Country

              Population,

              Mean BMI (kg/m2)

              Sweetener 1:

              Type,

              Quantity (g/d)

              Sweetener 2:

              Type,

              Quantity (g/d)

              Daily Diet

              (carbohydrate/

              fat/protein)

              Study design,

              Follow-up,

              Sample size

              Mean age (y),

              % female

              Allocation concealment,

              Jadad score,

              Funding

              Non-caloric versus Saccharide

              Reid [61]

              2007

              UK

              General

              23

              Aspartame

              3.56

              Sucrose

              42

              Ad lib

              RCT

              4 wk

              133

              32

              100

              Unclear

              1

              Public

              Raben [63]

              2002

              Denmark

              Overweight

              28

              Aspartame/Acesulfame/

              Cyclamate/Saccharin

              0.48-0.67

              Sucrose

              125-175

              Ad lib

              RCT

              10 wk

              41

              35

              85

              Unclear

              1

              Mixeda

              Chantelau [62]

              1985

              Germany

              DM1

              < 25

              Cyclamate

              348 mg

              Sucrose

              24

              Restricted to no other

              added sweeteners however sucrose-sweetened soft drinks were discouraged

              xRCT

              2 4wk periods

              10

              Range 25-43

              80

              Unclear

              1

              -

              Saccharide versus Saccharide

              Okuno [68]

              2010

              Japan

              General

              23

              Isomaltulose/

              Sucrose

              40

              Sucrose

              40

              Ad lib

              RCT

              12 wk

              50

              53

              80

              Unclear

              2

              Private

              Tudor Ngo Sock [64]

              2010

              Netherlands

              General

              19-25

              Fructose

              3.5 g/kg FFM

              Glucose

              3.5 g/kg FFM

              Total and distribution of energy restricted

              55/30/15%

              xRCT

              2 1wk periods

              (2-3wk wo)

              11

              25

              0

              Unclear

              1

              Mixed

              Yaghoobi [69]

              2008

              Iran

              Overweight/

              Obese

              31

              Honey

              70

              Sucrose

              70

              Ad lib

              RCT

              Max 30d

              55

              42

              56

              Unclear

              1

              Public

              Boesch [70]

              2001

              Switzerland

              General

              < 25

              Tagatose

              45

              Sucrose

              45

              Ad lib

              xRCT

              2 28d periods

              (28d wo)

              12

              Range 21-30

              0

              Inadequate

              2

              -

              Bantle [65]

              2000

              US

              General

              25

              Fructose

              80

              (incl 17 g glucose)

              Glucose

              80

              (incl 15 g fructose)

              Total and distribution of energy restricted

              55/30/15%

              xRCT

              2 42d periods

              24

              41

              50

              Unclear

              1

              Public

              Luo [71]

              2000

              Belgium

              DM2

              28

              FOS

              20

              Sucrose

              20

              Ad lib

              xRCT

              2 4wk periods

              (2wk wo)

              10

              57

              40

              Unclear

              1

              Private

              Alles [73]

              1999

              Netherlands

              DM2

              28

              FOS

              Saccharide

              30

              Glucose

              Saccharide

              8

              Ad lib

              xRCT

              2 20d periods

              20

              59

              55

              Unclear

              1

              Mixed

              Luo [72]

              1996

              France

              General

              21

              FOS

              20

              Sucrose

              20

              Low-fiber diet

              recommended

              xRCT

              2 4wk periods

              (2wk wo)

              12

              24

              0

              Unclear

              2

              Private

              Bantle [67]

              1986

              US

              50% DM1/50% DM2

              -

              Sucrose

              23%

              Fructose

              21%

              Total and distribution of energy restricted

              55/30/15%

              xRCT

              2 8d periods

              24

              43

              54

              Unclear

              1

              Mixed

              Macdonald [66]

              1973

              UK

              General

              -

              Sucrose

              6.5 g/kg

              Glucose

              6.5 g/kg

              Restricted to

              1 g/kg calcium

              caseinate

              xRCT

              2 11d periods

              (2wk wo)

              10

              Range 20-25

              40

              Unclear

              1

              Private

              UK, United Kingdom; US, United States; DM1, type 1 diabetes mellitus; DM2, type 2 diabetes mellitus; HFCS, high fructose corn syrup; FOS, fructooligosaccharide; FFM, fat free mas;, xRCT, controlled crossover trial; RCT, parallel randomized controlled trial; wo, washout; max, maximum; "-" means the value was not reported in the study

              aBoth public and private sources of funding

              Four trials were in diabetic populations [62, 67, 71, 73], seven trials were in generally healthy populations [61, 6466, 68, 70, 72] and two trials were in overweight/obese [69] or overweight [63] populations. Mean BMI levels ranged from 21 to 31 kg/m2. Median mean age was 35 years and median sex distribution was 54% women.

              Sample size ranged from 10 to 133 (median 20), 1 had a sample size ≥ 30 per group and duration of follow-up ranged from 1 to 12 weeks (median 4 weeks). Ten were crossover trials [62, 6467, 7073] and four were parallel trials [61, 63, 68, 69]. Jadad scores ranged from 1 to 2 (median 1). Twelve of thirteen trials did not report whether or how treatment assignment was concealed. One used alternating assignments according to body weight [70].

              Non-caloric versus saccharide: effects on weight management, blood glucose and blood lipids

              Two trials reported change in BMI (Table 5). The 4-week trial in healthy participants [61] did not find a significant loss in BMI in non-caloric sweetener recipients (-0.3 kg/m2 (-1.1,0.5), 133 participants). The trial in overweight participants [63] found a significantly greater loss in BMI over ten weeks of follow-up in participants consuming the non-caloric sweetener (-0.9 kg/m2 (-1.5,-0.4), 41 participants). Two trials reported absolute change in weight. One crossover trial was done in type 1 diabetic participants and found no difference in weight loss between groups over four weeks (0.8 kg (-3.3,4.9), ten participants [62]). The other trial in overweight participants [63] found significantly greater weight loss over 10 weeks in the non-caloric sweetener group (-2.6 kg (-3.7,-1.5), 41 participants).
              Table 5

              Weight management, blood glucose and blood lipids: Non-caloric versus Sucrose

              Non-caloric

              sweetener

              Population

              Timepoint (week)

              No of participants

              MD (95% CI)

              BMI, kg/m 2

              Aspartame

              General

              4

              133

              -0.3 (-1.1,0.5)

              Mixturea

              Overweight

              10

              41

              -0.9 (-1.5,-0.4)

              Weight, kg

              Cyclamate

              DM1

              4

              10

              0.8 (-3.3,4.9)

              Mixture

              Overweight

              10

              41

              -2.6 (-3.7,-1.5)

              Day Energy Intake, kcal

              Aspartame

              General

              4

              133

              -283 (-414,-153)

              Mixture

              Overweight

              10

              41

              -491 (-806,-177)

              HbA1C, %

              Cyclamate

              DM1

              4

              10

              -0.02 (-0.4,0.3)

              HOMA Index

              Mixture

              Overweight

              10

              41

              -0.20 (-0.58,0.18)

              Total Cholesterol, mmol/L

              Cyclamate

              DM1

              4

              10

              -0.34 (-0.87,0.19)

              HDL Cholesterol, mmol/L

              Cyclamate

              DM1

              4

              10

              -0.05 (-0.32,0.22)

              Triglycerides, mmol/L

              Cyclamate

              DM1

              4

              10

              -0.02 (-0.16,0.12)

              Mixture

              Overweight

              10

              41

              -0.26 (-0.85,0.34)

              aAspartame, acesulfame, cyclamate, saccharin

              DM1, Type 1 Diabetes Mellitus; DM2, Type 2 Diabetes Mellitus; BMI, Body mass index; HbA1C, Glycated haemoglobin; HOMA, Homeostatic Model Assessment; MD, Mean difference; CI, Confidence interval

              Statistically significant results are bolded.

              Two trials reported energy intake; both reported a significant effect of non-caloric sweeteners. The 4-week trial in generally healthy participants [61] found a significantly reduced intake of calories in non-caloric sweetener participants (-283 kcal (-414,-153), 133 participants).The trial in overweight participants [63] also found significantly less energy intake (over one day) in the non-caloric sweetener group after ten weeks of follow-up (-491 kcal (-806,-177), 41 participants).

              Available trials found no effect of sweetener type on HbA1C (one trial: -0.02% over four weeks (-0.40,0.30), ten participants [62]) or the HOMA index (one trial: -0.20 over ten weeks (-0.58,0.18), forty-one participants [63]). The trial in ten type 1 diabetic participants [62] found no effect on total cholesterol, HDL cholesterol, or triglycerides over the course of four weeks; the other trial in forty-one overweight participants [63] found no effect on triglycerides over the course of ten weeks.

              Saccharide versus saccharide: effects on weight management, blood glucose and blood lipids

              Two trials reported change in BMI (Table 6); one comparing honey to sucrose in overweight/obese participants over 4 weeks of follow-up [69]; the other comparing a mixture of isomaltulose and sucrose to sucrose over 12 weeks of follow-up [68] in healthy participants. Neither found a significant difference between sweeteners. One trial compared FOS to glucose [73] (three weeks in twenty diabetic participants) and one trial compared FOS to sucrose [72] (four weeks in twelve healthy participants), respectively. Neither found a difference in absolute weight change. Five other trials done in varying populations (including overweight/obese [69] or healthy populations [6466, 68]) found no differences in change in absolute weight between sweeteners. Two trials reported energy intake (FOS compared with glucose [73] and sucrose [72] respectively, but neither found a significant difference.
              Table 6

              Weight management, blood glucose and blood lipids: Saccharide vs Saccharide

              Comparison

              Population

              Timepoint (week)

              No of participants

              MD (95% CI)

              BMI, kg/m 2

              Honey vs Sucrose

              Overweight/Obese

              4

              55

              -0.5 (-3.1,2.1)

              Isomaltulose/Sucrose vs Sucrose

              General

              12

              50

              -0.04 (-0.4,0.3)

              Weight, kg

              Fructose vs Glucose

              General

              6

              24

              0.1 (-3.4,3.6)

              Fructose vs Glucose

              General

              1

              11

              -0.4 (-3.1,2.3)

              FOS vs Glucose

              DM2

              3

              20

              0.2 (-5.2,5.6)

              FOS vs Sucrose

              General

              4

              12

              1.0 (-2.4,4.4)

              Honey vs Sucrose

              Overweight/Obese

              4

              55

              -1.5 (-6.9,3.9)

              Isomaltulose/Sucrose vs Sucrose

              General

              12

              50

              -0.06 (-0.9,0.8)

              Sucrose vs Glucose

              General

              2

              10

              0.2 (-0.07,0.4)

              Energy Intake, kcal

              FOS vs Glucose

              DM2

              3

              20

              -139 (-399,122)

              FOS vs Sucrose

              General

              4

              12

              -56 (-156,43)

              HbA1C, %

              FOS vs Sucrose

              DM2

              4

              10

              0.17 (-0.59,0.93)

              Isomaltulose/Sucrose vs Sucrose

              General

              12

              50

              0.01 (-0.05,0.07)

              HOMA Index

              Isomaltulose/Sucrose vs Sucrose

              General

              12

              50

              -0.44 (-0.76,-0.12)

              Total Cholesterol, mmol/L

              Fructose vs Glucose

              General

              1

              11

              0.10 (-0.24,0.44)

              FOS vs Glucose

              DM2

              3

              20

              0.20 (-0.27,0.67)

              FOS vs Sucrose

              DM2

              4

              10

              0.15 (-0.24,0.54)

              FOS vs Sucrose

              General

              4

              12

              0.31 (0.03,0.59)

              Honey vs Sucrose

              Overweight/Obese

              4

              55

              -0.11 (-0.26,0.05)

              Isomaltulose/Sucrose vs Sucrose

              General

              12

              50

              -0.10 (-0.17,-0.02)

              Tagatose vs Sucrose

              General

              4

              12

              -0.11 (-0.51,0.29)

              LDL Cholesterol, mmol/L

              Fructose vs Glucose

              General

              1

              11

              0 (-0.17,0.17)

              FOS vs Sucrose

              DM2

              4

              10

              0.13 (-0.21,0.47)

              Honey vs Sucrose

              Overweight/Obese

              4

              55

              -0.03 (-0.22,0.16)

              Isomaltulose/Sucrose vs Sucrose

              General

              12

              50

              -0.02 (-0.08,0.04)

              Tagatose vs Sucrose

              General

              4

              12

              0.09 (-0.26,0.44)

              HDL Cholesterol, mmol/L

              Fructose vs Glucose

              General

              1

              11

              0 (-0.17,0.17)

              FOS vs Sucrose

              General

              4

              12

              -0.06 (-0.14,0.02)

              FOS vs Sucrose

              DM2

              4

              10

              0.07 (-0.03,0.17)

              Honey vs Sucrose

              Overweight/Obese

              4

              55

              0.01 (-0.12,0.14)

              Isomaltulose/Sucrose vs Sucrose

              General

              12

              50

              -0.02 (-0.05,0.01)

              Tagatose vs Sucrose

              General

              4

              12

              -0.17 (-0.28,0.06)

              Triglycerides, mmol/L

              FOS vs Glucose

              DM2

              3

              20

              0.12 (-0.30,0.54)

              FOS vs Sucrose

              General

              4

              12

              0.18 (-0.03,0.39)

              FOS vs Sucrose

              DM2

              4

              10

              -0.18 (-0.38,0.02)

              Honey vs Sucrose

              Overweight/Obese

              4

              55

              -0.10 (-0.22,0.02)

              Isomaltulose vs Sucrose

              General

              12

              50

              -0.27 (-0.44,-0.10)

              *Aspartame, acesulfame, cyclamate, saccharin

              DM1 Type 1 Diabetes Mellitus, DM2 Type 2 Diabetes Mellitus, BMI Body mass index, HbA1C Glycated hemoglobin, HOMA Homeostatic Model Assessment, MD Mean difference, CI Confidence interval

              Statistically significant results are bolded.

              Two trials (one comparing FOS to sucrose [71] and one comparing isomaltulose/sucrose to sucrose [68]) found no significant effect on HbA1C. However, the latter [68] found a significant decrease in the HOMA index among isomaltulose/sucrose recipients (-0.44 (-0.76,-0.12)).

              Seven trials reported change in total cholesterol. The pooled result of two trials [71, 72] comparing FOS to sucrose was statistically significant (0.26 mmol/L (0.03,0.48), I2 = 0%, τ2 = 0 (0,0.01)), although this conclusion was based on a total of only twenty-two participants. One trial comparing isomaltulose and sucrose to sucrose (50 healthy participants over 12 weeks) [68] found a significantly smaller increase in total cholesterol for the isomaltulose/sucrose group (-0.10 mmol/L (-0.17,-0.02)). No trials found an effect of sweetener type on LDL cholesterol or HDL cholesterol. The trial comparing isomaltulose and sucrose to sucrose [68] also found a significant effect on triglycerides (-0.27 mmol/L (-0.44,-0.10), 0.11 decrease versus 0.16 mmol/L increase). However, four trials studying other combinations of sweeteners [69, 7173] found no effect of sweetener choice on triglyceride levels.

              Discussion

              To our knowledge, this is the first systematic review of randomized trial evidence that examines comparative sweetener effectiveness in diabetic, overweight/obese, and healthy populations. Despite tremendous interest in hypocaloric sweeteners as a potential tool to prevent obesity and its complications, we found little evidence to support their health benefits as compared to caloric alternatives. Based on analyses of two trials, we found that the inclusion of non-caloric sweeteners in the diet resulted in reduced energy intake compared to the caloric (sucrose) groups - approximately 500 kcal/day less over 10 weeks or 250 kcal/day over 4 weeks. The longer of these trials found that those in the non-caloric sweetener group also had a decrease in BMI compared to an increase in BMI in the sucrose group (-0.40 versus 0.50 kg/m2, and -1.00 versus 1.60 kg, respectively) [63]. Given that the control group was asked to ingest supplemental calories in addition to their regular ad lib diet, a BMI reduction of approximately1 kg/m2 over 10 weeks (or 0·1 kg/m2/week) may be overly optimistic. However, even a reduction in BMI of 0.05 kg/m2/week would be clinically relevant if sustained for a year or more. The remaining analyses comparing non-caloric and caloric sweeteners were non-significant.

              Main findings

              • 53 randomized controlled trials were included - all small and largely short-term (only 13 trials with ≥1 week durations)

              • 2-hour blood glucose (mixed evidence, τ2 = 3.66 (95% CI 1.66,7.31): fructose versus sucrose (MD -0.54 mmol/L (-1.06,-0.03)), fructose versus glucose (-0.89 mmol/L (-1.21,-0.59)), fructose versus other sugars (-0.85 mmol/L (-1.47,-0.21)) in non-diabetic participants

              • 2-hour blood glucose (direct evidence): fructose versus glucose (-4·81 mmol/L (-6.34,-3.29), I2 = 0%, τ2 = 0 (0,7.47), 5 trials in 52 diabetic participants)

              • change in BMI: non-caloric mixture versus sucrose (MD -0.9 kg/m2 [-1.5,-0.4], in 41 overweight participants, over 10 weeks), non-caloric aspartame versus sucrose (-0.3 kg/m2 (-1·1,0·5), 133 healthy participants, over 4 weeks)

              • energy intake (over one day): non-caloric aspartame versus sucrose (-283 kcal (-414,-153), 133 healthy participants, over 4 weeks), non-caloric mixture versus sucrose (-491 kcal (-806,-177), 41 overweight participants, over 10 weeks)

              • total cholesterol: FOS versus sucrose (0.26 mmol/L (0.03,0.48), I2 = 0%, τ2 = 0 (0,0.01), 2 trials with a total of 12 healthy and 10 type 2 diabetic participants, over 4 weeks)

              Head-to-head comparisons between saccharides did not identify any statistically significant differences. The confidence limits of these results either included minimally important differences or the group sizes were too small (< 30) to have good estimates of standard deviation [74]. The one exception was the comparison between sucrose and FOS, which suggested that total cholesterol was reduced to a greater extent with sucrose than with FOS. However, the confidence intervals for this analysis included values that were not clinically relevant (0.03 to 0.59 mmol/L). There was no evidence that HFCS or fructose increased levels of cholesterol relative to other sweeteners.

              Although we found that fructose reduced 2-hour blood glucose concentrations by 4.81 mmol/L compared to glucose in diabetic participants, data comparing non-caloric and sugar alcohols to the more commonly used sucrose or HFCS were inconclusive. Contrary to perception and current recommendations, no substantive evidence describing important long-term benefits of hypocaloric sweeteners for diabetic patients were identified. Also, despite popular belief, no high-quality RCT evidence was found indicating that fructose causes or exacerbates hypertriglyceridemia [6].

              Although the identified trials were numerous, they were very small and largely short-term. We found 13 trials with participant follow-up longer than 1 week and group sizes ≥ 10: 3 that compared non-caloric sweeteners to sucrose, and 10 that were head-to-head comparisons of saccharides. Ten of 13 trials had a Jadad score of 1 and none adequately concealed treatment assignment prior to assignment. Although blinding the participants would have been impossible in many of the trials due to taste differences between sweeteners [63], the reporting of important design descriptors were largely absent, indicating a substantial risk for bias [12, 13]. The longest trial was only 10 weeks - not long enough to determine whether substituting a non-caloric sweetener for a caloric sweetener is sustainable in daily practice. To detect an important reduction in weight over at least one year such as 2.5 kg/m2 (less than 0.05 kg/m2/week) in a RCT would require a minimum of 85 participants (assumptions: 25% loss-to-follow-up, α = 0.05, power = 90%, SD = 3 kg/m2).

              Our network meta-analysis had several limitations: 1) the sugar alcohol and other sugar categories contained multiple sweeteners that are likely to have different blood glucose profiles thereby inducing heterogeneity, 2) power to detect inconsistency is limited by the number of trials included in each test, and 3) the back-calculation method used to detect inconsistency involved multiple tests thereby increasing the false-positive rate. However, we did not detect any inconsistency.

              Another limitation was that only three studies restricted the total energy consumed by each participant. Therefore, participants may have supplemented energy lost with non-caloric sweeteners with other food products - sweetened or otherwise. However, it may be argued that this is a strength of the trials - in that they reflect what happens in real world self-management diet practices. Lastly, and perhaps most importantly, all studies were small, thereby underestimating standard deviation and as a result underestimating confidence interval widths and increasing the likelihood of false-positive findings [74]. Despite this, the confidence intervals for many analyses were wide and did not exclude a minimally important difference. Small study bias (or publication bias) may also play a role in our findings concerning longer-term outcomes.

              In theory, substituting non-caloric and lower caloric sweeteners for simple sugars should reduce energy intake and thereby the risk of obesity and its consequences. However, there are a number of reasons why increasing use of non-caloric and lower caloric sweeteners might not lead to the expected improvements in energy regulation. First, use of hypocaloric sweeteners might not induce weight loss even in the short term. For example, if reductions in calories due to sweeteners are offset by increases in caloric intake from other sources [75, 76], or offset by decreases in caloric expenditure [77, 78]. Although our data suggest that non-caloric sweeteners may lead to clinically relevant weight loss through reduced energy consumption, this conclusion was driven by a single trial with a total of 41 participants. Unlike caloric sweeteners (which may partially compensate added calories with reduced energy intake from other sources) [79], non-caloric sweeteners are not known to suppress appetite, and therefore would not reduce the motivation to eat. Furthermore, it has been suggested that the psychobiological signals with non-caloric sweeteners may directly influence physiological regulatory mechanisms and thus further reduce their potential for reducing net energy intake [75, 80]. Second, if calorie reduction is not maintained, short-term reductions in weight due to the use of hypocaloric sweeteners might not be sustained. Third, it is possible though speculative that any health benefits due to weight loss from non-caloric sweeteners might be wholly or partially offset by currently unrecognized adverse events due to their use. The lack of data on the long-term benefits of non-caloric sweeteners means that it is currently impossible to determine whether these substances will improve public health.

              Conclusions

              In summary, despite the public health importance of obesity, and obesity-related chronic diseases (for example, diabetes); the clear role of excessive caloric intake in these conditions; and the billions of dollars spent on non-caloric sweeteners [4, 5], little high-quality clinical research has been done to identify the potential harms and benefits of hypocaloric sweeteners. Since even small reductions (as little as 6%) in body-weight can prevent chronic disease [81, 82], hypocaloric sweeteners could play an important role in a wider population health strategy to prevent, reduce and manage obesity-related comorbidities. Eliminating unnecessary added sweeteners from food products (for example, buns, crackers, and processed meats) and substituting sugars with lower calorie sweeteners in foods such as desserts and drinks could significantly improve health. Long-term, high-quality, adequately powered randomized controlled trials are required to confirm this hypothesis by assessing the clinically relevant outcomes reported in this review.

              Abbreviations list

              ADA: 

              American Diabetes Association

              ADI: 

              Acceptable Daily Intake

              BMI: 

              body mass index

              CPG: 

              Clinical Practice Guideline

              FOS: 

              fructooligosaccharide

              HbA1C: 

              glycated haemoglobin

              HDL: 

              high density lipoprotein

              HFCS: 

              high fructose corn syrup

              HOMA: 

              Homeostatic Model Assessment

              LDL: 

              low density lipoprotein

              MCMC: 

              Markov chain Monte Carlo

              MD: 

              mean difference

              RCT: 

              randomized controlled trial

              SD: 

              standard deviation.

              Declarations

              Acknowledgements

              The authors of this report are grateful to Dale Storie for librarian support and to Natasha Krahn, Nicola Hooton, and Sophanny Tiv for additional reviewer support, and Ghenette Houston for administrative support. Support for this work was provided in part through an Interdisciplinary Team Grant to the Interdisciplinary Chronic Disease Collaboration from the Alberta Heritage Foundation for Medical Research (AHFMR). AHFMR was not involved in the interpretation of results or the drafting of the manuscript.

              Authors’ Affiliations

              (1)
              Department of Medicine, University of Alberta
              (2)
              Department of Agricultural, Food & Nutritional Science, University of Alberta
              (3)
              Department of Pediatrics, University of Alberta

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