Reducing the Sugar Burden using Non-Nutritive Sweeteners: Review of Evidence and Recommendations

    

    

    Figure 1:  Flow diagram of the literature search of the systematic review.
    
    

Evidence addressing specific concerns with non-nutritive sweeteners

Influence of NNS on sweet taste cravings: Studies reported that NNS may prevent individuals from associating sweetness with caloric intake and, as a result, alter their intake, craving more sweet food and choosing this over nutritionally valuable food, contributing to weight gain [50,51]. Similarly, some articles on rodents showed that when they were exposed to NNS, either in utero or through breastfeeding, they exhibited heightened preferences for NNS in adulthood [58-60]. On the other hand, current evidence from adult and paediatric cohorts, does not show any consistent association between NNS intake and increased cravings for sugar or sweet products and suggests that NNS usage tends to lower the intake of sweet-tasting substances, suggesting a potential role in satisfying the desire for sweetness [61]. A recent systematic review by Appleton KM et al. [62] confirmed that the available evidence does not indicate that repeated exposure to sweetness can lead to habituation of sweet taste in children or adults [62]. The latter review also reported that exposure to sweet tastes from dietary sources with low quantities of sugars, for example those sweetened with NNS, may not only replace consumption of free sugars but could also reduce the desire for sweetness [62]. Additionally a recent meta-analysis of clinical studies on NNS and sweetness concluded that NNS may offer, to some extent, the advantage of satisfying desire for sweetness when consumed shortly before or with a meal [63]. A study supported by the Netherlands Organization for Health Research and Development in 4-12 year old children found that NNS consumption tends to reduce, rather than increase, the intake of sugar-containing foods and facilitates weight loss, as indicated by reduced weight gain and fat accumulation in normal-weight children [64]. Another study among 7-11 year old Dutch primary school children showed that sugar-sweetened and sugar-free beverages produced similar satiety, and children consuming sugar-free beverages did not make up for the missing calories from other sources [65]. This perhaps explains why the sugar-free group had less body fat than the sugar group [65].

Safety of NNS in pregnant and lactating women: Data reviewed by Araujo JR et al. [66] concluded that animal studies showed longterm consumption of NNS, particularly aspartame, starting during the peri-gestational period, may predispose the offspring to develop obesity and metabolic syndrome later in life [66]. However, the authors expressed caution in extrapolation to humans since welldesigned clinical studies evaluating NNS metabolic effects in humans are still lacking [66]. In the review by Sylvetsky et al. [58] it was also determined that NNS ingested by lactating mothers are passed to their infants in breast milk [58]. However, the author raised concern as to whether the concentration of NNS found in breast milk exerts any biological effects [58]. This requires further study. Leading global dietary authorities such as the US FDA, EFSA, FSANZ, HC, and JECFA have confirmed the safety of all approved NNS for all population groups, including pregnant and breastfeeding women [52]. They noted that the available data do not suggest any adverse effects such as increased risk of toxicity, adverse pregnancy outcomes or neonatal issues when NNS is substituted for sugar in pregnancy within the established ADI [67,68]. Other published reviews did not find a clear relationship between early sweet taste experiences (from fruit and vegetable extracts & sweetened water) in utero and during early infancy, and later acceptance for sweet taste [69].

Impact of NNS on glycaemic response: The past decade was marked by significant interest in the ability of NNS to have an adverse effect on blood glucose control [43]. Grotz VL et al. [43] conducted a literature search and found that there were some studies which hypothesized that sucralose and other NNS can adversely affect blood glucose regulation, e.g., by affecting total insulin secretion, glucose uptake and/or glucose utilization either by direct effect or via effects on glucagon-like peptide-1 or gastric inhibitory polypeptide [43]. However the authors suggest that these studies were mostly conducted in animals, and testing methodologies and other factors may limit reliability of extrapolating results of studies in animals to overall effects on blood glucose control in humans [43]. On the contrary, multiple trials across the globe have provided evidence in support of NNS; claiming they do not affect postprandial blood glucose levels or promote insulin secretion in humans [27,43,70-73].

In parallel, several human studies in children and healthy, normoglycemic, normal-weight adult cohorts, as well as at-risk, diabetic, and overweight populations, demonstrate that NNS do not have any adverse impact on glucose uptake and glycaemic control [40,43,74-84]. Several meta-analyses support the inert nature of NNS with respect to glycemic control [51,71,73]. There is also a lack of evidence from human in vivo studies for any clinical effect of NNS on the secretion of incretins [76].

Role of NNS in diabetes management

A systematic review by Romo-Romo A et al. [71] included observational studies, clinical trials and meta-analyses, and assessed the association between NNS consumption and the development of metabolic diseases including type 2 diabetes, obesity, and metabolic syndrome [71]. The authors observed that some studies suggest an association between NNS consumption and development of metabolic diseases; however, the authors concluded that the evidence level of observational studies cannot establish causality [71]. Additionally, they also concluded the results obtained from clinical trials are contradictory, due to the heterogeneity in the population included, NNS studied, placebo use, exposure time and outcomes evaluated [71].

Alternatively, several health organisations globally such as the American Diabetes Association (ADA), EFSA, Academy of Nutrition and Dietetics in the US, and Diabetes UK recognise the role of NNS as a safe replacement to added sugar in healthy and diabetic populations [27,85,86].

In the US, a study by Anton et al. [83] in 2010 showed that sucralose, aspartame and stevia, decrease blood glucose and insulin response compared to sucrose, and concluded that stevia preloads significantly reduced postprandial glucose levels compared to sucrose preloads (p<0.01), and postprandial insulin levels compared to both aspartame and sucrose preloads (p<0.05) [83].

Results from the 2001-2012 NHANES showed that the consumption of NNS beverages compared to water was associated with reduced intake of carbohydrates and sugar, with no adverse relationships to glycaemic responses [87]. Other systematic reviews and meta-analysis of RCTs showed that NNS consumption was not found to elevate blood glucose level [88].

Effect of NNS on weight gain, obesity and cardiometabolic risks

The potential effects on weight gain, body composition and obesity in human and animal studies were reviewed by Archibald AJ et al. [89]. The study provided an overview of the current body of literature regarding prenatal and childhood exposure to NNS worldwide. It reported that “there is an emerging body of evidence from human and animal studies suggesting that early-life exposure to NNS may have adverse effects on cardio-metabolic health and development possibly leading to increased risk of obesity-related outcomes”. However, the authors noted that some studies found no association, or at least did not provide evidence of confounding variables, thus they concluded that “current evidence remains inconclusive due to the paucity of RCTs, lack of evidence from low and middle-income countries, limitations of observational studies, and lack of mechanistic studies” [89].

Some of the available literature on animal and limited human studies raise a concern regarding the increased weight gain and adverse cardiometabolic risks of NNS [90-93]. Azad M.B et al. [94] published a systematic review in 2017 to determine whether routine consumption of NNS was associated with long-term adverse cardiometabolic effects. The authors found that the evidence from RCTs did not clearly support the intended benefits of NNS for weight management, and observational data suggested that routine intake of NNS may be associated with increased BMI and cardio metabolic risk [94]. However, this observation has been addressed by Sievenpiper, J. L. K. et al. [95] who highlighted that important methodological considerations were overlooked in this systematic review. Furthermore, they noted that the findings were discordant with higher quality evidence from RCTs and were at high risk of reverse causality, among other important limitations, including publication bias, inconsistency, indirectness and imprecision in the pooled estimates [95]. Additionally, Nakajima, KI et al. [96] suggested that a potentially overlooked factor that might influence the effect of NNS on cardiometabolic health may be the timing of ingestion [96]. Evidence from well-designed studies shows that NNS beverages do not negatively impact the cardiometabolic risk factors [97].

In a review evaluating the latest research on the effects of NNS on the host microbiome, the gut-brain axis, glucose homeostasis and energy consumption; as well as their potential impact on obesity, Pearlman M et al. [98] noted that NNS are marketed as a healthy alternative to sugar and as a tool for weight loss. However, the authors acknowledged that many of the studies evaluating the effects of NNS on metabolic parameters were using rodent models, and although these models provide some insight into the effects of NNS, the outcomes are inconsistent in humans [98].

A brief report “NNS: Disturbing the Energy Balance Equation in Adolescents?” was published on obesity in December 2017. The authors modelled dietary intake data collected for 2-19 year olds participating in the 2009-2010, 2011-2012, and 2013-2014 NHANES. Interestingly, the study results indicated that NNS beverage consumption is associated with obesity in US adolescents but showed no association between consumption of NNS foods and obesity. The authors did not discuss additional correlations that were identified in their models and concluded that observational findings should be further investigated to determine if NNS intake is related to obesity [99]. In addition, the authors noted that the study relied on selfreported dietary recall and there were differences in reporting by older children and parents of young children. They concluded that the observational nature of this study excludes any determination of relationship between cause and effect [99].

Comparing the efficacy of NNS or water for weight loss during a 12-week behavioural weight loss treatment program, Peters J.C et al. [100] suggested that NNS beverages can be part of an effective weight loss strategy. An article by Anton S.D. [101], however, suggested that these findings should be interpreted with caution, since longer term outcomes would be required to confirm these results and the potential mechanism(s) for the superior effects of NNS on weight loss outcomes observed in the original study remain unknown. Results from an additional one year RCT suggested that NNS beverages may be an effective tool for weight loss and maintenance within the context of a weight management program [102]. This result is consistent with the few other published long-term human trials that evaluated NNS for weight loss [103,104].

Evidence from well-designed, controlled human studies consistently showed that the consumption of NNS and/or foods and drinks containing them can be a useful tool in managing or lowering excess body weight [64,83,103-106]. Systematic reviews and metaanalyses of human studies also support these results [63,107,108]. A recent meta-analysis by Miller PE et al. [107] provided a rigorous evaluation of the scientific evidence on NNS and body weight and composition. The authors concluded that the findings from observational studies showed no association between NNS intake and body weight or fat mass; however, they also noted that the data from RCTs, which provide the highest quality evidence for examining the potentially causal effects of NNS intake, indicates that substituting NNS options for regular-calorie versions, results in a modest weight loss and may be a useful dietary tool to improve compliance with weight loss or weight maintenance plans [107]. Similarly, a metaanalysis conducted by de La Hunty et al. [108] demonstrated that using foods and drinks sweetened with aspartame instead of sucrose results in a significant reduction in both energy intake and body weight [108].

Assessment of cancer risk with NNS usage

According to the currently available literature, the possible link between NNS and cancer seems to be negligible [21,102-113]. Early studies on cyclamate suggested that when it was given in combination with saccharin it caused bladder cancer in laboratory animals [121]. However subsequent carcinogenicity studies turned out to be negative [103,116]. As association between sucralose and cancer has also been proposed [122], however, this too is unsubstantiated [110].

Three case-control studies have shown no overall excess of bladder cancer in association with use of NNS, nearly all of which contained saccharin [111]. Epidemiological studies in humans did not find the bladder cancer-inducing effects of saccharin and cyclamate that had been reported from animal studies in rats [123]. Saccharin has been extensively researched; over 5000 patients with bladder cancer have participated in case-control studies over 27,000 diabetics have been observed for 234,000 person-years. The cumulative relative risk from these case control studies is less than 0.98, while the standardized mortality ratio for bladder cancer in diabetics is only 70. After Analyzing these studies the authors concluded that saccharin is not related to human bladder cancer [124]. Additionally, a review of epidemiologic evidence conducted by Marinovich M et al. [112] found no consistent association between the use of aspartame and cancer risk [112]. Health authorities such as US FDA, WHO, EFSA, National Cancer Institute (NCI) have noted, on many occasions, that NNS are safe and do not cause cancer.

Contribution of NNS to dental health

Oral health-related diseases such as dental caries are on a rapid rise in the Middle East region, largely attributed to poor awareness as well as contributing factors such as increased sugar consumption, inadequate oral hygiene practices and a high prevalence of smoking [125]. Carbohydrates present in the mouth are fermented by naturally occurring bacteria, resulting in the production of acid that leads to demineralization of the teeth and caries. NNS, however, cannot be metabolized by oral bacteria to form acids. This lack of sugar-related fermentation may offer protection from dental caries [126]. NNS are even utilised to improve the palatability of toothpastes, mouthwashes and fluoride supplements, thereby encouraging greater use. Indeed, the EFSA has approved the claim that chewing gum with NNS helps maintain tooth mineralisation and neutralise acids [127].

Limitations

The main aim of our review was an attempt to create an awareness in MENA region regarding NNS and specific concerns regarding their usage. However, there was no region-specific data available and hence articles were chosen to give a global perspective to the reader. Only English language articles were considered during literature review.

Conclusion

Following this review of available literature, NNS may appear to be safe for use as a sugar replacement, when used within the ADI limits. NNS may be effective in reducing energy intake, not increasing the sugar cravings and lowering the glycaemic response. They are also considered to be safe for consumption by pregnant and lactating women by leading global dietary authorities. Data also suggests they are safe for use by diabetic and obese individuals. They do not cause dental caries and the claims of possible risk of NNS to induce cancer are not substantiated by the available evidence. However, specific safety profiles for individual NNS need to be considered by healthcare professionals before making any recommendations. In the ME region, there are increased rates of obesity and associated NCDs. High sugar intake, which in turn leads to high calorie intake, is one of the major causes of these diseases. NNS could be a means of tackling the issue of sugar burden in the MENA region.

It is clear that more region-specific studies are needed on sugar and NNS intake, and their association with obesity, metabolic risk factors, cardiovascular diseases and cancer, with the aim of generating culturally-specific, evidence-based recommendations for sugar intake reduction. Given their prevalence and widespread use, NNS and their physiological impact, remains an important topic of research. It is therefore important to caution against potential hazards or risks of NNS usage. Community education and awareness are crucial for disseminating the potential role of NNS as a safe alternative to sugar. Recommendations are needed for the industry when it comes to product’s reformulation along with guidelines on packaging such as declaration of the chemical composition of the NNS in use.

Acknowledgment

The review of scientific evidence, conclusions and recommendations presented in this paper were discussed and formulated at a consensus meeting in Dubai, UAE. All authors received support to travel and attend the meeting from PepsiCo, Inc. Dr. Sanjith Soman of MullenLowe Middle East compiled the comments of the authors and supported the writing of this paper. The work of Dr. Sanjith Soman was funded by PepsiCo, Inc. The views expressed in this paper are those of the authors without any participation or involvement of PepsiCo, Inc. or its employees.

Author Contributions

N.H. outlined and drafted the manuscript. A.A.D., K.A.-M., W.H.A., M.M.E.-D., L.C.I., S.M.S. provided critical comments and concepts during the meeting that were incorporated into the manuscript. They also reviewed and revised the draft manuscript and approved the submitted version.

Conflicts of Interest

Each author received travel expenses and an honorarium for participating in the consensus meeting sponsored by PepsiCo, Inc, held on 4th May 2018, in Dubai, UAE.

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