Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

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

  • Natasha Wiebe1,
  • Raj Padwal1,
  • Catherine Field2,
  • Seth Marks3,
  • Rene Jacobs2 and
  • Marcello Tonelli1Email author
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.
https://static-content.springer.com/image/art%3A10.1186%2F1741-7015-9-123/MediaObjects/12916_2011_Article_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.

https://static-content.springer.com/image/art%3A10.1186%2F1741-7015-9-123/MediaObjects/12916_2011_Article_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/m2

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/m2

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, 410 Agriculture/Forestry Centre, University of Alberta
(3)
Department of Pediatrics, 8213 Aberhart Centre, University of Alberta

References

  1. Parker KJ: Alternatives to sugar. The search for an ideal non-nutritive sweetener is almost a century old. Nature. 1978, 271: 493-495.PubMedView Article
  2. The straight facts on sweeteners. [http://​www.​thecoca-colacompany.​com/​ourcompany/​pdf/​sweetener_​fact_​sheet.​pdf]
  3. Sugar substitutes. [http://​www.​pepsiproductfact​s.​com/​sugarsub.​php]
  4. Lipson E: Chapter 1: Executive Summary. Trends in the US market for sugar, sugar substitutes, and sweeteners. Edited by: Packaged Facts. 2008, 1-26.
  5. Freedonia: Freedonia focus on food and beverage additives. 2010, The Freedonia Group I
  6. Sievenpiper JL, Carleton AJ, Chatha S, Jiang HY, de Souza RJ, Beyene J, Kendall CW, Jenkins DJ: Heterogeneous effects of fructose on blood lipids in individuals with type 2 diabetes: systematic review and meta-analysis of experimental trials in humans. Diabetes Care. 2009, 32: 1930-1937.PubMedPubMed CentralView Article
  7. Vermunt SH, Pasman WJ, Schaafsma G, Kardinaal AF: Effects of sugar intake on body weight: a review. Obes Rev. 2003, 4: 91-99.PubMedView Article
  8. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M, Finnish Diabetes Prevention Study Group: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001, 344: 1343-1350.PubMedView Article
  9. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002, 346: 393-403.PubMedView Article
  10. Gougeon R, Spidel M, Lee K, Field CJ: Canadian Diabetes Association National Nutrition Committee Technical Review: Non-nutritive intense sweeteners in diabetes management. Canadian Journal of Diabetes. 2004, 28: 385-399.
  11. Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009, 339: b2535.PubMedPubMed CentralView Article
  12. Jadad AR, Moore RA, Carrol D, Jenkinson C, Reynolds JM, Gavaghan DJ, McQuay HJ: Assessing the quality of reports of randomized clinical trials: Is blinding necessary?. Control Clin Trials. 1996, 17: 1-12.PubMedView Article
  13. Schulze KF, Chalmers I, Hayes RJ, Altman DG: Empirical evidence of bias. JAMA. 1995, 273: 408-412.View Article
  14. Cho MK, Bero LA: The quality of drug studies published in symposium proceedings. Ann Intern Med. 1996, 124: 485-489.PubMedView Article
  15. Wiebe N, Vandermeer B, Platt RW, Klassen TP, Moher D, Barrowman NJ: A systematic review identifies a lack of standardization in methods for handling missing variance data. J Clin Epidemiol. 2006, 59: 342-353.PubMedView Article
  16. Egger M, Davey Smith G, Schneider M, Minder C: Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997, 315: 629-634.PubMedPubMed CentralView Article
  17. Renwick AG, Molinary SV: Sweet-taste receptors, low-energy sweeteners, glucose absorption and insulin release. Br J Nutr. 2010, 104: 1415-1420.PubMedView Article
  18. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR: Chapter 16: Identifying and quantifying heterogeneity. Introduction to Meta-Analysis. 2009, Wiley, 123: 124.View Article
  19. Lu G, Ades AE: Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med. 2004, 23: 3105-3124.PubMedView Article
  20. Introduction to mixed treatment comparisons. [https://​www.​bris.​ac.​uk/​cobm/​docs/​intro%20​to%20​mtc.​doc]
  21. Dias S, Welton NJ, Caldwell DM, Ades AE: Checking consistency in mixed treatment comparison meta-analysis. Stat Med. 2010, 29: 932-944.PubMedView Article
  22. Prat-Larquemin L, Oppert JM, Bellisle F, Guy-Grand B: Sweet taste of aspartame and sucrose: effects on diet-induced thermogenesis. Appetite. 2000, 34: 245-251.PubMedView Article
  23. Melchior JC, Rigaud D, Colas-Linhart N, Petiet A, Girard A, Apfelbaum M: Immunoreactive beta-endorphin increases after an aspartame chocolate drink in healthy human subjects. PhysiolBehav. 1991, 50: 941-944.
  24. Gonzalez-Ortiz M, Ramos-Zavala MG, Gonzalez-Lopez RC, Robles-Cervantes JA, Martinez-Abundis E, Gonzalez-Ortiz M, Ramos-Zavala MG, Gonzalez-Lopez RC, Robles-Cervantes JA, Martinez-Abundis E: Effect of 2 liquid nutritional supplements for diabetes patients on postprandial glucose, insulin secretion, and insulin sensitivity in healthy individuals. JPEN J Parenter Enteral Nutr. 2009, 33: 67-70.PubMedView Article
  25. Horwitz DL, McLane M, Kobe P: Response to single dose of aspartame or saccharin by NIDDM patients. Diabetes Care. 1988, 11: 230-234.PubMedView Article
  26. Nguyen NU, Dumoulin G, Henriet MT, Berthelay S, Regnard J: Carbohydrate metabolism and urinary excretion of calcium and oxalate after ingestion of polyol sweeteners. J Clin Endocrinol Metab. 1993, 77: 388-392.PubMed
  27. Hassinger W, Sauer G, Cordes U, Krause U, Beyer J, Baessler KH: The effects of equal caloric amounts of xylitol, sucrose and starch on insulin requirements and blood glucose levels in insulin-dependent diabetics. Diabetologia. 1981, 21: 37-40.PubMedView Article
  28. Rizkalla SW, Luo J, Wils D, Bruzzo F, Slama G: Glycaemic and insulinaemic responses to a new hydrogenated starch hydrolysate in healthy and type 2 diabetic subjects. Diabetes Metab. 2002, 28 (5): 385-390.PubMed
  29. Wheeler ML, Fineberg SE, Gibson R, Fineberg N: Metabolic response to oral challenge of hydrogenated starch hydrolysate versus glucose in diabetes.[see comment]. Diabetes Care. 1990, 13: 733-740.PubMedView Article
  30. Maki KC, Kanter M, Rains TM, Hess SP, Geohas J: Acute effects of low insulinemic sweeteners on postprandial insulin and glucose concentrations in obese men. Int J Food Sci Nutr. 2009, 60 (SUPPL 3): 48-55.PubMedView Article
  31. Teff KL, Grudziak J, Townsend RR, Dunn TN, Grant RW, Adams SH, Keim NL, Cummings BP, Stanhope KL, Havel PJ: Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: influence of insulin resistance on plasma triglyceride responses. J Clin Endocrinol Metab. 2009, 94: 1562-1569.PubMedPubMed CentralView Article
  32. Bowen J, Noakes M, Clifton PM: Appetite hormones and energy intake in obese men after consumption of fructose, glucose and whey protein beverages. Int J Obes. 2007, 31: 1696-1703.View Article
  33. Chong MF, Fielding BA, Frayn KN, Chong MFF, Fielding BA, Frayn KN: Mechanisms for the acute effect of fructose on postprandial lipemia. Am J Clin Nutr. 2007, 85: 1511-1520.PubMed
  34. Visvanathan R, Chen R, Garcia M, Horowitz M, Chapman I: The effects of drinks made from simple sugars on blood pressure in healthy older people.[see comment]. Br J Nutr. 2005, 93: 575-579.PubMedView Article
  35. Teff KL, Elliott SS, Tschop M, Kieffer TJ, Rader D, Heiman M, Townsend RR, Keim NL, D'Alessio D, Havel PJ: Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab. 2004, 89: 2963-2972.PubMedView Article
  36. Vozzo R, Baker B, Wittert GA, Wishart JM, Morris H, Horowitz M, Chapman I: Glycemic, hormone, and appetite responses to monosaccharide ingestion in patients with type 2 diabetes. Metabolism. 2002, 51: 949-957.PubMedView Article
  37. Spiller GA, Moynihan S, Butterfield G: Effects of sun-dried raisins on serum glucose: support for a convenient, plant-based snack food. Vegetarian Nutr. 1998, 2: 93-95.
  38. Stewart SL, Black RM, Wolever TMS, Anderson GH: The relationship between glycaemic response to breakfast cereals and subjective appetite and food intake. Nutr Res. 1997, 17: 1249-1260.View Article
  39. Blaak EE, Saris WHM: Postprandial thermogenesis and substrate utilization after ingestion of different dietary carbohydrates. Metabolism. 1996, 45: 1235-1242.PubMedView Article
  40. Fukagawa NK, Veirs H, Langeloh G: Acute effects of fructose and glucose ingestion with and without caffeine in young and old humans. Metabolism. 1995, 44: 630-638.PubMedView Article
  41. Schwarz JM, Schutz Y, Piolino V, Schneider H, Felber JP, Jequier E: Thermogenesis in obese women: effect of fructose vs. glucose added to a meal. Am J Physiol. 1992, 262: E394-E401.PubMed
  42. Bukar J, Mezitis NH, Saitas V, Pi-Sunyer FX: Frozen desserts and glycemic response in well-controlled NIDDM patients. Diabetes Care. 1990, 13: 382-385.PubMedView Article
  43. Georgakopoulos K, Katsilambros N, Fragaki M, Poulopoulou Z, Kimbouris J, Sfikakis P, Raptis S: Recovery from insulin-induced hypoglycemia after saccharose or glucose administration. Clin Physiol Biochem. 1990, 8: 267-272.PubMed
  44. Schwarz JM, Schutz Y, Froidevaux F, Acheson KJ, Jeanpretre N, Schneider H, Felber JP, Jequier E: Thermogenesis in men and women induced by fructose vs glucose added to a meal. Am J Clin Nutr. 1989, 49: 667-674.PubMed
  45. Simonson DC, Tappy L, Jequier E, Felber JP, DeFronzo RA: Normalization of carbohydrate-induced thermogenesis by fructose in insulin-resistant states. Am J Physiol. 1988, 254: E201-E207.PubMed
  46. Jansen RW, Penterman BJ, van Lier HJ, Hoefnagels WH: Blood pressure reduction after oral glucose loading and its relation to age, blood pressure and insulin. Am J Cardiol. 1987, 60: 1087-1091.PubMedView Article
  47. Tappy L, Randin JP, Felber JP, Chiolero R, Simonson DC, Jequier E, DeFronzo RA: Comparison of thermogenic effect of fructose and glucose in normal humans. Am J Physiol. 1986, 250: E718-724.PubMed
  48. Samanta A, Burden AC, Jones GR: Plasma glucose responses to glucose, sucrose, and honey in patients with diabetes mellitus: an analysis of glycaemic and peak incremental indices. Diabet Med. 1985, 2: 371-373.PubMedView Article
  49. Bantle JP, Laine DC, Castle GW, Thomas JW, Hoogwerf BJ, Goetz FC: Postprandial glucose and insulin responses to meals containing different carbohydrates in normal and diabetic subjects. N Engl J Med. 1983, 309: 7-12.PubMedView Article
  50. Crapo PA, Scarlett JA, Kolterman OG: Comparison of the metabolic responses to fructose and sucrose sweetened foods. Am J Clin Nutr. 1982, 36: 256-261.PubMed
  51. Mann JI, Truswell AS, Pimstone BL: The different effects of oral sucrose and glucose on alimentary lipaemia. Clin Sci. 1971, 41: 123-129.PubMedView Article
  52. Van Can JGP, Ijzerman TH, Van Loon LJC, Brouns F, Blaak EE: Reduced glycaemic and insulinaemic responses following isomaltulose ingestion: Implications for postprandial substrate use. Br J Nutr. 2009, 102: 1408-1413.PubMedView Article
  53. Qin LQ, Li J, Wang Y, Wang PY, Sato A, Kaneko T: Effect of repeated intake of disaccharides on glucose metabolism and insulin secretion in healthy adults - Comparison between sucrose and maltose. J Health Sci. 2003, 49: 226-228.View Article
  54. Stanhope KL, Griffen SC, Bair BR, Swarbrick MM, Keim NL, Havel PJ: Twenty-four-hour endocrine and metabolic profiles following consumption of high-fructose corn syrup-, sucrose-, fructose-, and glucose-sweetened beverages with meals. Am J Clin Nutr. 2008, 87: 1194-1203.PubMedPubMed Central
  55. Melanson KJ, Zukley L, Lowndes J, Nguyen V, Angelopoulos TJ, Rippe JM: Effects of high-fructose corn syrup and sucrose consumption on circulating glucose, insulin, leptin, and ghrelin and on appetite in normal-weight women. Nutrition. 2007, 23: 103-112.PubMedView Article
  56. Kawai K, Yoshikawa H, Murayama Y, Okuda Y, Yamashita K: Usefulness of palatinose as a caloric sweetener for diabetic patients. Horm Metab Res. 1989, 21: 338-340.PubMedView Article
  57. Erkelens DW, Stofkooper A, Van DBE, Van D: Glycaemic effect of mono-, di- and polysaccharides in a mixed meal in diabetic patients. Neth J Med. 1985, 28: 157-163.PubMed
  58. Grysman A, Carlson T, Wolever TM, Wolever TMS: Effects of sucromalt on postprandial responses in human subjects. Eur J Clin Nutr. 2008, 62: 1364-1371.PubMedView Article
  59. Munstedt K, Sheybani B, Hauenschild A, Bruggmann D, Bretzel RG, Winter D: Effects of basswood honey, honey-comparable glucose-fructose solution, and oral glucose tolerance test solution on serum insulin, glucose, and C-peptide concentrations in healthy subjects. J Med Food. 2008, 11: 424-428.PubMedView Article
  60. Bowker SL, Majumdar SR, Johnson JA: Systematic review of indicators and measurements used in controlled studies of quality improvement for type 2 diabetes. Can J Diabetes. 2005, 29: 230-238.
  61. 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. Br J Nutr. 2007, 97: 193-203.PubMedView Article
  62. 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: 204-207.PubMedView Article
  63. 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. Am J Clin Nutr. 2002, 76: 721-729.PubMed
  64. Ngo Sock ET, Le KA, Ith M, Kreis R, Boesch C, Tappy L: Effects of a short-term overfeeding with fructose or glucose in healthy young males. Br J Nutr. 2010, 103: 939-943.PubMedView Article
  65. Bantle JP, Raatz SK, Thomas W, Georgopoulos A: Effects of dietary fructose on plasma lipids in healthy subjects. Am J Clin Nutr. 2000, 72: 1128-1134.PubMed
  66. Macdonald I, Taylor J: Differences in body weight loss on diets containing either sucrose or glucose syrup. Guys Hosp Rep. 1973, 122: 155-159.PubMed
  67. Bantle JP, Laine DC, Thomas JW: Metabolic effects of dietary fructose and sucrose in types I and II diabetic subjects. JAMA. 1986, 256: 3241-3246.PubMedView Article
  68. Okuno M, Kim MK, Mizu M, Mori M, Mori H, Yamori Y: Palatinose-blended sugar compared with sucrose: different effects on insulin sensitivity after 12 weeks supplementation in sedentary adults. Int J Food Sci Nutr. 2010, 61: 643-651.PubMedView Article
  69. Yaghoobi N, Al-Waili N, Ghayour-Mobarhan M, Parizadeh SM, Abasalti Z, Yaghoobi Z, Yaghoobi F, Esmaeili H, Kazemi-Bajestani SM, Aghasizadeh R, Saloom KY, Ferns GA: Natural honey and cardiovascular risk factors; effects on blood glucose, cholesterol, triacylglycerole, CRP, and body weight compared with sucrose. ScientificWorldJournal. 2008, 8: 463-469.PubMedView Article
  70. Boesch C, Ith M, Jung B, Bruegger K, Erban S, Diamantis I, Kreis R, Bar A: Effect of oral D-tagatose on liver volume and hepatic glycogen accumulation in healthy male volunteers. Regul Toxicol Pharmacol. 2001, 33: 257-267.PubMedView Article
  71. Luo J, Van Yperselle M, Rizkalla SW, Rossi F, Bornet FR, Slama G: Chronic consumption of short-chain fructooligosaccharides does not affect basal hepatic glucose production or insulin resistance in type 2 diabetics. J Nutr. 2000, 130: 1572-1577.PubMed
  72. Luo J, Rizkalla SW, Alamowitch C, Boussairi A, Blayo A, Barry JL, Laffitte A, Guyon F, Bornet FR, Slama G: Chronic consumption of short-chain fructooligosaccharides by healthy subjects decreased basal hepatic glucose production but had no effect on insulin-stimulated glucose metabolism. Am j clin nutr. 1996, 63: 939-945.PubMed
  73. Alles MS, de Roos NM, Bakx JC, van de Lisdonk E, Zock PL, Hautvast GA: Consumption of fructooligosaccharides does not favorably affect blood glucose and serum lipid concentrations in patients with type 2 diabetes. Am J Clin Nutr. 1999, 69: 64-69.PubMed
  74. Pearson ES: The application of statistical methods to industrial standardization and quality controls. 1960, London, UK: B.S. 600, British Standards Institution
  75. Bellisle F, Drewnowski A: Intense sweeteners, energy intake and the control of body weight. Eur J Clin Nutr. 2007, 61: 691-700.PubMedView Article
  76. Smeets PA, de Graaf C, Stafleu A, van Osch MJ, van der Grond J: Functional magnetic resonance imaging of human hypothalamic responses to sweet taste and calories. Am J Clin Nutr. 2005, 82: 1011-1016.PubMed
  77. Tam J, Fukumura D, Jain RK: A mathematical model of murine metabolic regulation by leptin: energy balance and defense of a stable body weight. Cell Metab. 2009, 9: 52-63.PubMedPubMed CentralView Article
  78. Sullivan EL, Cameron JL: A rapidly occurring compensatory decrease in physical activity counteracts diet-induced weight loss in female monkeys. Am J Physiol Regul Integr Comp Physiol. 2010, 298: R1068-1074.PubMedPubMed CentralView Article
  79. Erlanson-Albertsson C: How palatable food disrupts appetite regulation. Basic Clin Pharamcol Toxicol. 2005, 97: 61-73.View Article
  80. 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: 459-466.PubMedView Article
  81. Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, Schoelles K: Bariatric surgery: a systematic review and meta-analysis. JAMA. 2004, 292: 1724-1737.PubMedView Article
  82. Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH: The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009, 9: 88.PubMedPubMed CentralView Article
  83. Gougeon R, Spidel M, Lee K, Field CJ: Canadian Diabetes Association National Nutrition Committee Technical Review: Non-nutritive Intense Sweeteners in Diabetes Management. Can J Diabetes. 2004, 28: 385-399.
  84. Wolever T, Barbeau M, Charron S, Harrigan K, Leung S, Madrick B, Taillefer T, Seto C: Guidelines for the nutritional management of diabetes mellitus in the new millennium: A position statement by the Canadian Diabetes Association. Can J Diabetes Care. 1999, 23: 56-69.
  85. Calorie Control Council. [http://​www.​caloriecontrol.​org/​sweeteners-and-lite]
  86. Powers MA, Crapo PA: The fructose story. Diabetes Educ. 1982, 7: 22-25.PubMedView Article
  87. Lycasin maltitol syrups. [http://​www.​roquette-food.​com/​delia-CMS/​search_​product/​topic_​id-1720/​article_​id-3653/​product_​id-1208/​]
  88. Glucerna 1.2 Cal Monograph. [http://​abbottnutrition.​com/​Downloads/​Gluc-1_​2-Cal.​pdf]
  89. Sweeteners. [http://​www.​elmhurst.​edu/​~chm/​vchembook/​549sweet.​html]
  90. Carbohydrates and the sweeteners of honey. [http://​www.​honey.​com/​nhb/​technical/​technical-reference/​]
  91. PALATINOSE™ -The functional carbohydrate providing better energy. [http://​www.​beneo-palatinit.​com/​en/​Food_​Ingredients/​Isomaltulose/​What_​is_​Isomaltulose/​Palatinose-Brochure_​EN_​1.​pdf]
  92. Trehalose. [http://​www.​caloriecontrol.​org/​sweeteners-and-lite/​sugar-substitutes/​other-sweeteners/​trehalose]
  93. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1741-7015/​9/​123/​prepub

Copyright

© Wiebe et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement