Review of the nutritional benefits and risks related to intense sweeteners

The exhaustive review included 10,989 manuscripts (9,965 in English and 1024 in non-English
languages). Out of them, 9,373 were excluded after a reading of the title and the
abstract. Consequently, 1,616 full-text manuscripts have been extensively reviewed
of which 383 (all in English) have been considered of interest for the topic of benefits
and risks related to IS. For this review however, only the most relevant ones have
been quoted, mainly based on their methodology, novelty and originality. Among these
studies, 30.1 % were funded by the industry, 56.3 % by non-profit organisations, and
the others did not report funding sources. However, we did not consider differently
studies based the funding source.

Effects on eating behaviour and taste preferences

IS are often consumed as sugar substitutes, particularly in beverages, in order to
satisfy a desire for sweetness while avoiding energy intake from sugars. The expert
appraisal assessed whether there were metabolic consequences of this separation of
sweetness and calorie intake, particularly in terms of body’s ability to associate
a taste with an energy value and therefore regulate its energy balance, and also in
terms of consequences of IS consumption on appetite for sweetness and the consumption
of sweet products.

Data in adults

A meta-analysis covering studies undertaken before 2006 along with around ten randomised
experimental studies were identified to address these points. The meta-analysis of
15 randomised experimental studies 9] assessed the effects of aspartame consumed alone or with other (unspecified) IS on
food and energy intake during the course of a day in adults. These measurements covered
a limited number of subjects (less than 30) and highly variable time periods of a
few days to 16 weeks. The main inclusion criterion for studies in this meta-analysis
was the measurement of food intakes for at least 24 hours, to assess the full extent
of any compensatory effects of the various meals consumed over the day. The authors
conclude that consuming aspartame as a sugar substitute results in a decrease of daily
energy intake by 220 Kcal on average. Moreover, the authors indicate that this substitution
may be more efficient in beverages than in solid foods, since the energy supplied
by liquids leads to less satiety than that supplied by solid foods. In fact, the estimated
compensation rate is thought to be lower for sugars consumed in liquid form than in
solid form 10]. Therefore, according to these authors, the reduction in energy intake due to the
replacement of sugar with sweeteners is greater with artificially sweetened beverages
than with artificially sweetened solid foods. However, the conclusions of this meta-analysis
should be treated with caution, due to several methodological limitations, particularly
a lack of essential information on the study selection process, the assessment of
their quality and the statistics applied to assess the heterogeneity of the data taken
into account. Other experimental studies (that were not included in the meta-analysis
since they covered periods of less than 24 hours) analysed the effects of IS on appetite
and food intake. These studies used an IS preload approximately one hour before a
meal, generally in beverage form (rarely in solid form, i.e. in a food), and measured
food intake and calorie intake during the next meal. All of these studies showed that
irrespective of the nature of the tested IS, a preload reduced the sensation of hunger
and the desire to eat, with a maximum effect immediately after its consumption. However,
this effect tended to disappear before the start of the meal, which explains why most
studies did not observe reduced food intake during the meal after the preload. Regarding
food preferences, several studies assessed the effect of IS on the perception of sweetness
(gustatory stimuli) and/or taste preferences for foods. Several studies showed that
preference for a sweet food was independent of the sweetening agent (i.e. no difference
between an IS and sucrose), but their results differed as to the repercussions of
this preference on consumption of this food. However, these studies had extremely
variable protocols and objectives, to the extent that it is difficult to compare their
results and draw an overall conclusion on the effect of IS on food preferences.

Overall, based on studies dealing with occasional exposure to an IS before a meal,
it is not possible to infer the effect of regular IS consumption on sweetness habituation
or increased cravings for sweetened products. Most experimental studies show that
the occasional consumption of IS before or during a meal has no effect on food intake
or energy intake during the next meal. Occasional IS consumption before a meal reduces
the sensation of hunger and the desire to eat, just like caloric sweeteners, but this
effect is temporary and disappears before the start of the meal. In most cases, the
use of IS as sugar substitutes results in a decrease in short-term energy intake due
to their low calorie content and the lack of compensation. However, the available
data cover insufficient time periods to guarantee the maintenance of this effect over
the medium or long term.

Data in children

Preference for sweetness is innate. It is strong at birth and then tends to decrease.
However, it seems to be maintained by the repeated consumption of sweetened foods
or beverages during early childhood 11]. A study 12] showed that adding aspartame or sucrose to milk favoured its consumption. Moreover,
the work of Birch and their collaborators revealed that children preferred flavours
associated with calorie intake, suggesting that sweetness itself is not sufficient
to generate food preferences, and that energy density, just as much as (or even more
than) sweetness, can determine food preferences 13], 14]. However, there are no data showing whether IS have a specific effect, in relation
to caloric sweeteners, on the development of taste and food preferences. A study compared
the effects of consuming 250 mL daily of artificially sweetened beverages vs sugar-sweetened beverages on the satiety and desire to eat of children aged seven
to 11 years for 18 months 15]. The level of satiety was the same, irrespective of the beverage consumed.

In conclusion, based on the available studies, it is not possible to determine whether
IS consumed during early childhood have a specific effect on the development of taste
and food preferences or on the short- and medium-term regulation of food intake.

Effects on body weight and composition

IS are commonly used by consumers as sugar substitutes as part of weight-loss diets
or to control energy intake and prevent weight gain.

Data in adults

Two meta-analysis (Table 2) 9], 16], a systematic review 17] and several original articles 18]–29]examined the relationship between IS consumption and changes in body composition and
weight. A meta-analysis 30] took into account observational studies (with nine articles included) and randomised
controlled trials (RCTs, with 15 articles included) in adults and children. The section
on observational studies showed no relationship between IS consumption and changes
in body weight or fat mass but showed a slight increase in BMI (+0.03 kg/m
²
on average). The section on RCTs showed that replacing sugars with IS in sweet products
resulted in moderate weight loss (with an estimated average effect of 0.8 kg) and
a decrease in BMI (-0.24 kg/m
²
on average) for time periods ranging from three weeks to 18 months. This meta-analysis,
of good methodological quality, highlights the extreme variability of results from
studies with a similar design (whether RCT or observational) and the differences in
results between observational studies and RCTs. In the meta-analysis by De la Hunty
9], eight studies on very heterogeneous populations (people with energy restrictions
and unrestricted diets, normal-weight and obese people, in normal living conditions
and in metabolic chambers) were included. According to the authors, the effect of
IS on weight loss is significant. They extrapolate the theoretical reduction of 220 kcal/day
related to the replacement of sugars with aspartame over the long term, and by postulating
its maintenance over time, calculate that this reduction could result in weight loss
of 0.2 kg per week. However, the methodological weaknesses of this meta-analysis has
to be emphasised, particularly the lack of essential information related to the study
selection process and the statistics applied to assess heterogeneity. The systematic
review by Wiebe et al. (2011) cites two intervention studies comparing the effects
of artificially sweetened drinks and sugar-sweetened drinks on BMI 31],32]. These studies, focusing on different populations (normal-weight women in one and
overweight women in the other), had different results (no effect in normal-weight
women, reduced weight in overweight women). Five other randomised controlled trials
21], 24], 25], 27], 29] were identified. They were all undertaken in overweight subjects and the majority
focused on very small populations (between 20 and 50 subjects). Two demonstrated modest
weight loss of 1.2 and 1.5 kg on average, but the other three, including the one with
the largest study population (n?=?318), did not show any effects on weight loss related to the consumption of artificially
sweetened beverages compared to the consumption of sugar-sweetened beverages or water.
There are also seven prospective observational epidemiological studies with highly
heterogeneous results. One study did not show any association between IS consumption
and changes in body composition 23]; four studies reported a positive association, i.e. a significantly higher body weight
or waist size in IS consumers 18]–20],28]; and two studies reported a negative association 22], 26].

Table 2. methodology of the meta-analyses on the effect of intense sweeteners on body composition.

In conclusion, observational and intervention studies report contradictory associations
between IS consumption and weight loss. Therefore, no conclusion can be drawn as to
the long-term effect of replacing caloric sweeteners with IS on the weight of regular
adult consumers of sweet products.

Data in children

Four RCT studies focusing on the relationship between IS consumption and body composition
were identified. In three of these studies, changes in weight and BMI did not differ
between IS consumers and non-consumers 33]–35]. These studies focused on overweight or obese children and had methodological limitations.
The fourth study, of good methodological quality, examined the effects of consuming
250 mL/day of an artificially sweetened drink, compared to the same amount of sugar-sweetened
drink, in 641 normal-weight children (aged four to 12 years), who were regular consumers
of sugar-sweetened drinks, for 18 months 36]. This study showed a significant decrease in the BMI z-score (the most relevant criterion
to assess changes in corpulence in growing children) in the group that consumed artificially
sweetened drinks. The change in body weight between the two groups differed by 1 kg
on average. Of the seven prospective epidemiological studies in children, five 37], 38] observed a positive relationship between IS consumption (primarily in beverage form)
and weight over time, while two 37] did not find any relationship. To explain these findings, the authors of these studies
assumed that subjects ‘at risk for weight gain’ or with less healthy food profiles
were those who consumed the most IS in order to reduce their energy intake.

Most of the prospective observational studies undertaken in children show that IS
use is paradoxically associated with weight gain, although the causality of this relationship
has not been established. The four available controlled trials showed conflicting
results but none reported weight gain. No conclusions can be drawn from all of these
studies as to the significance of IS for weight management in children and adolescents.

Effects on blood glucose and type 2 diabetes

This section presents data on the effects of IS consumption on glucose homeostasis
and risk of diabetes, in healthy subjects, type 1 diabetics and type 2 diabetics Thirty-one
clinical trials and two reviews assessed the short-term effects (less than one week)
of IS consumption on glucose homeostasis. To date, the data on the long-term risk
of developing diabetes are still limited and have been taken from seven observational
epidemiological studies.

Effects on glucose homeostasis

Regarding the acute effects (i.e. less than 24 hrs.), the available studies did not
show any effects related to the consumption of aspartame on an empty stomach 39]–44], saccharine 45] or sucralose 46], 47] on blood glucose and insulin levels. Other studies assessed acute effects of IS on
post-prandial glycaemic parameters after a test meal 48]–52]. These studies generally showed that consuming IS before a test meal did not modify
post-prandial glycaemic and insulin responses compared to a placebo, and reduced these
responses compared to a sucrose preload. These effects were reported irrespective
of the tested IS (aspartame, stevia extract, sucralose, beverage containing acesulfame
K and sucralose). It should also be noted that the parameters of these studies were
highly variable with differences in the composition of test meals, the time between
the preload and the meal, the studied subject groups (age, sex, healthy overweight
or obese subjects) and the preload form (solid or liquid). Several studies also showed
that consuming IS before a meal resulted in increased secretion of GLP1 (Glucagon-like
peptide), a gastro-intestinal hormone that usually increases insulin secretion, slows
down gastric emptying and reduces glucagon secretion 53]. This increase in GLP1 may be induced by IS activating sweetness receptors, as suggested
by data in rats 54].

When considering short- and medium-term effects, several studies assessed the effect
of regular IS intake (one to three times per day, for a few days to several weeks),
in capsule form or in beverages, on maintaining blood sugar control (glucose and insulin
concentrations measured after a night of fasting, glycated haemoglobin HbA1c). For
type 2 diabetics, the consumption of sucralose 55] or aspartame 56]–58] for periods of up to 18 weeks did not change fasting glucose levels) compared to
sucrose or a placebo. Furthermore, fasting plasma glucose and insulin, and HOMA-IR
(insulin sensitivity calculated from the HOMA index) were not modified in non-diabetic
obese subjects who had consumed a beverage sweetened with aspartame for six months
compared to groups who had consumed sugar-sweetened drinks, water or milk 21]. Other studies covering unspecified IS compared to sucrose in obese or overweight
subjects 59] confirm these results. Regarding stevia extracts, the data show either a lack of
effect on glucose control in healthy 59] or diabetic 59] subjects or a slight significant decrease in blood glucose levels in healthy subjects
59] or hypertensive subjects 60].

Overall, the vast majority of studies do not show any acute effects of IS intake on
blood glucose or insulin concentrations measured on an empty stomach or after a test
meal, in healthy subjects or in diabetics. Some studies reported a modest increase
in GLP-1 secretion, but with no repercussions on insulin secretion or blood glucose
concentrations. IS consumption has no effect on short- and medium-term blood glucose
parameters in healthy subjects or in diabetics.

Effects on the risk of type 2 diabetes (T2D)

The seven observational studies dealing with IS consumption and the incidence of T2D
showed diverging results. Four cohort studies of good quality (three undertaken in
North American populations and one in a European population), over periods of nine
to 24 years, did not show any relationship between the consumption of artificially
sweetened beverages and the risk of developing T2D after adjustment for BMI and energy
intake of subjects 61]–63], 26]. Three other cohort studies suggested a positive association between the consumption
of artificially sweetened beverages and the incidence of T2D 64]–66]. Among them a French study, 64], showed that the incidence of T2D was significantly higher (HR (95 % CI) 2.21 [1.56-3.14])
in the group of women consuming the largest amounts of artificially sweetened beverages
(over 600 mL per week) who were monitored for 14 years, with a linear and dose-dependent
relationship. The second study, undertaken in the United States for seven years, reported
an increase in the incidence of T2D in subjects consuming more than one artificially
sweetened beverage per day in a model with adjustment for the primary confounding
factors (HR (95 % CI) 1.67 [1.27–2.20]. The third study, which reported an increased
incidence of T2D in subjects consuming more than one artificially sweetened beverage
per week (HR (95 % CI) 1.70 [1.13–2.55], focused on a limited-sized Japanese population
not representative of the general population, monitored for seven years. It is important
to underline the heterogeneity of these data, particularly in terms of the characteristics
of the populations and the monitoring periods (from seven to 24 years). Furthermore,
in these studies, the consumption of artificially sweetened beverages was recorded
when the subjects were first included, often through self-administered frequency questionnaires,
with no updating of dietary data over time.

In conclusion, the long-term epidemiological studies on the risk of developing T2D
show heterogeneous results, but the most robust studies do not report any effects.

Other effects

Effects on lipid parameters

Of the 20 randomised controlled experimental studies analysed, the majority focused
on aspartame or stevia extracts. Compared to a placebo, aspartame consumption had
no effects on triglycerides or cholesterol concentrations (either total, HDL, LDL
or VLDL cholesterol) in various populations (healthy, T2D and overweight subjects)
for periods ranging from 13 to 28 weeks. Compared to a caloric sweetener (sucrose,
glucose or fructose), of the five identified studies, two showed a modest significant
improvement in lipid profile (TG and/or total cholesterol) in the group that received
aspartame, still with no differences compared to the placebo. Three studies, two in
T2D patients, assessed the effect of stevia extracts on lipid parameters and showed
no differences compared to a placebo. Studies using other types of IS (cyclamate,
sucralose, IS mixture or unspecified IS) also showed no effects on the assessed lipid
parameters. Of the four identified cohort studies, most showed no effects on lipid
parameters related to the consumption of artificially sweetened beverages. A single
study reported a positive association between the consumption of these beverages and
an increase in TG concentrations associated with a lowering of HDLc 67].

In conclusion, the majority of observational studies showed no effects on lipid profile
related to IS. Two studies reported that replacing sugars with aspartame reduced plasma
triglyceride concentrations but the data are too limited to conclude that IS have
a beneficial effect on lipid profile.

Effects on pre-term deliveries

Two epidemiological studies are available. In the first 68], a dose-effect relationship was observed, which meant that the risk of pre-term delivery
was higher in the heaviest consumers of artificially sweetened beverages (OR (95 %
CI) 1.38 [1.15-1.65] for???1 serving of artificially sweetened carbonated soft drinks/d).
In addition to this Danish study, another study, with a similar methodology and including
over 60,000 pregnant women, suggested that the consumption of artificially sweetened
beverages and sugar-sweetened beverages was associated with an increased risk of spontaneous
or induced pre-term delivery (OR (95 % CI) 1.11 [1.00-1.24] for???1 serving of artificially
sweetened soft drinks/d). However, although the association was stronger for sugar-sweetened
beverages, the authors concluded that they could not determine whether this risk was
caused by the effects of these beverages or by other associated dietary or socio-economic
factors 69].

Based on the available data, it is not possible to identify any benefits or draw any
conclusions regarding the risk related to the consumption of intense sweeteners during
pregnancy, in terms of maternal health, obstetrical parameters or newborn health.

Effects on cancer

The relationship between IS consumption and cancer in humans was assessed in 55 scientific
studies. Thirty-nine of these studies involved the urinary tract and 32 focused exclusively
on bladder cancer. The other studies assessed the relationship between IS consumption
and the risk of brain cancer (four studies), digestive system cancer (six studies)
or other cancers (five studies). Except in the studies focusing on bladder cancer,
the IS in question were not identified by the authors. The relationship between saccharine
consumption and bladder cancer was the most commonly studied, given that data were
available in rodents 70]. The results of studies in humans are conflicting. Based on the analysis of data
in humans, it is not possible to determine a relationship (whether for saccharine
or for the other studied IS), since the studies did not adjust their results for major
confounding factors such as exposure to chemical pollutants. Regarding kidney, brain,
digestive system and breast cancers, the data are more limited and do not show any
relationship with IS consumption. A recent cohort study examining the risk of lymphoma
and leukaemia suggested an increased risk of non-Hodgkin lymphomas and multiple myelomas
in males consuming more than one serving (355 mL) per day of artificially sweetened
beverages and in the heaviest consumers of aspartame (as a table-top sweetener and
in beverages) compared to non-consumers 71]. No significant association was reported in women. The authors specified that due
to the differences in the results by sex, the results should be interpreted with caution.
Moreover, this study did not take into account exposure to chemical pollutants as
a confounding factor. However, it is worth noting that this study attempted to take
into account, in its statistical analysis, changes in the individual consumption of
artificial sweeteners over time, although little information is available regarding
the methodology.

On the whole, the epidemiological studies do not show any effects of IS consumption
on cancer risk. Only one recent study suggested a relationship between the consumption
of beverages containing IS and the occurrence of non-Hodgkin lymphomas and myelomas,
and additional studies are required.

Neurological effects

Regarding the potential neurological effects of IS, only aspartame has been studied.
There are two studies in healthy adults 72], 73]. No effects of aspartame on the measured parameters (reaction time, headaches, hunger,
sedation, electroencephalographic parameters) were observed. The study undertaken
in epileptic subjects 74] showed no statistically significant difference between aspartame and the placebo
on the incidence of epileptic seizures. The four available studies on migraine subjects
75]–78] show conflicting results. However, no conclusion can be drawn due to their poor methodological
quality (no adjustment) and the subjective nature of the measured effects (using non-validated
self-questionnaires). Regarding children, there are two studies, one in epileptic
children 79] and the other in hyperactive children 80], showing no significant effects of aspartame.

Some studies with significant methodological limitations suggested that aspartame
consumption may be involved in triggering epileptic seizures and migraines but no
conclusions can be drawn regarding the occurrence of such a risk from the data as
a whole.