Why is there a confusion about sweeteners’ role in weight and glucose control?

Science news from the FINUT 2020 virtual Conference


  • Conflicting outcomes between controlled clinical trials and observational studies are often the cause of confusion about low/no calorie sweeteners’ effects on health.
  • Limitations of observational study design do not allow to draw conclusions on cause-and-effect relationships, while randomised controlled studies offer higher quality evidence.
  • When interpreting research outcomes, the role of the comparator is key: sweeteners’ beneficial role is shown in studies comparing them to sugars, while no effect is found when compared to water or placebo (no calories removed from the diet).

The FINUT 2020 Conference that was organised as an online scientific event by the Ibero-American Nutrition Foundation (Fundación Iberoamericana de Nutrición – FINUT) gave us the opportunity to attend an interactive virtual meeting with experts. Dr Brian Cavagnari, Argentine Catholic University (UCA), Argentina, and Dr Hugo Laviada-Molina, Marist University of Mérida, Mexico, interpreted the science around low/no calorie sweeteners from an evidence-based perspective.

In nutrition science what matters most is the quality, not the quantity of studies

In this virtual meeting with the experts, Dr Cavagnari and Dr Laviada-Molina discussed why there is a controversy about the role of low/no calorie sweeteners in obesity and diabetes.1,2 The vast majority of randomised controlled trials (RCTs) find beneficial effects of low/no calorie sweeteners on reducing calorie intake and body weight, when these are used to replace sugars in the diet.3,4 On the other hand, observational studies show mixed outcomes, with some reporting a negative or neutral and others a positive association between low/no calorie sweeteners’ consumption and higher incidence of obesity or diabetes.5,6 However, Dr Cavagnari emphasised that association does not equal causation, which means that the observed positive association in some observational studies might be the outcome of reverse causality: people living with obesity or diabetes usually turn to sugar alternatives in their effort to reduce their calorie and sugar intakes and therefore to help them manage their weight or blood glucose levels. Also, this type of study design cannot take into consideration all confounding factors. While the most carefully designed prospective cohort studies may reduce or take into account many potential confounding factors, these can never be eliminated from observational studies.

Responding to an interesting question from participants, Dr Cavagnari pointed out that, in nutrition science, recommendations should be based on the best available evidence. While of course all study designs are important in helping research advance and in enhancing our scientific knowledge, evidence from RCTs is ranked higher compared to evidence from epidemiological research, according to the hierarchy of evidence (evidence-based medicine). Therefore, when evaluating the totality of available data on a scientific topic, it is not only a matter of the quantity of the published studies, but most importantly of their quality.

Low/no calorie sweeteners compared to sugar or placebo: the comparator matters

Clinical studies examining the effects of low/no calorie sweeteners on health outcomes such as body weight and glucose control follow various methodologies, with different study designs, duration of the intervention, measure outcomes and comparators. Regarding the latter, both speakers stressed that comparing low/no calorie sweeteners to a caloric comparator (e.g. sugar) versus to water or placebo leads to different results. In trials where non caloric sweeteners’ effects are compared to sugars, or in studies where low/no calorie sweetened products replace sugary drinks, the results almost consistently show a favourable effect of low/no calorie sweeteners in helping reduce total energy intake and body weight.3 Meta-analyses of such studies show that low/no calorie sweeteners lead to a moderate weight loss of approximately 2-2,5kg in people with overweight and obesity.4,6 It is also established that low/no calorie sweeteners cause a lower rise in blood glucose levels when used instead of sugars.7 In contrast, when low/no calorie sweeteners are compared to water or placebo, they have a neutral effect on glucose control, as it should normally be expected.8,9 Dr Laviada-Molina explained that these ingredients are food additives with no intrinsic pharmacological effects, meaning that, by themselves, they do not decrease blood glucose levels nor cause weight loss. Their favourable effect relates to the level of sugar substitution and to the fact that they help people adhere to a healthier, low-calorie, low-sugar diet.

The nature of the comparator is also important in meta-analyses of RCTs. When pooling together results from different studies, these should be assessed in groups according to the comparator. For example, meta-analyses5,6 of RCTs that merged trials with different comparators in the same analysis (with or without calorie displacement) found no or a less significant beneficial effect on body weight outcomes compared to meta-analyses3,4 that followed the recommended categorisation by comparator. Similarly, a recent meta-analysis of nine trials by Lohner and colleagues10 on the use of low/ no calorie sweeteners in diabetes, found no significant effect on glycaemic control considering mostly trials that compared low/no calorie sweeteners to water or placebo (six RCTs), while only three RCTs used sugar as a comparator (one without carbohydrate displacement). Dr Laviada-Molina highlighted that in their analysis, Lohner and colleagues included studies that were not designed properly to respond to the question people with diabetes need to know: whether low/no calorie sweeteners have a beneficial effect when used in place of sugar.

Concluding his presentation, Dr Laviada-Molina presented the outcomes of the consensus of the Latin-American Association of Diabetes (Asociación Latinoamericana de Diabetes (ALAD))2 which acknowledges the fact that the consumption of low/no calorie sweeteners is safe within the Acceptable Daily Intake (ADI) levels and which supports the assertion that their use can have benefits in calorie reduction, weight loss and glucose control, when used to replace sugar in the context of a structured dietary plan.

  1. Cavagnari BM. Edulcorantes no calóricos y peso corporal. (Non-caloric sweeteners and body weight). MEDICINA (Buenos Aires) 2019; 79: 115-122
  2. Laviada-Molina H, Escobar-Duque ID, Pereyra E, et al. Consenso de la Asociación Latinoamericana de Diabetes sobre uso de edulcorantes no calóricos en personas con diabetes. Rev ALAD 2018; 8: 152-74
  3. Rogers PJ, Hogenkamp PS, de Graaf K, et al. Does low-energy sweetener consumption affect energy intake and body weight? A systematic review, including meta-analyses, of the evidence from human and animal studies. Int J Obes 2016; 40(3): 381-94
  4. Laviada-Molina H, Molina-Segui F, Pérez-Gaxiola G, et al. Effects of nonnutritive sweeteners on body weight and BMI in diverse clinical contexts: Systematic review and meta-analysis. Obesity Reviews 2020; 21(7): e13020
  5. Azad MB., Abou-Setta AM., Chauhan BF., et al. Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. Canadian Medical Association Journal, 2017; 189(28): E929-E939
  6. Toews I, Lohner S, de Gaudry DK, Sommer J, Meerpohl JJ. Association between intake of non-sugar sweeteners and health outcomes: systematic review and meta-analyses of randomised and non-randomised controlled trials and observational studies. BMJ 2019; 363: k4718
  7. EFSA Scientific opinion on the substantiation of health claims related to intense sweeteners. EFSA 2011 Journal 9(6): 2229, and 9(4): 2076
  8. Nichol AD, Holle MJ, An R. Glycemic impact of non-nutritive sweeteners: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr 2018; 72: 796-804
  9. Greyling A, Appleton KM, Raben A, Mela DJ. Acute glycemic and insulinemic effects of low-energy sweeteners: a systematic review and meta-analysis of randomized controlled trials. American Journal of Clinical Nutrition 2020; 112(4): 1002-1014. nqaa167. https://doi.org/10.1093/ajcn/nqaa167
  10. Lohner S, Kuellenberg de Gaudry D, Toews I, Ferenci T, Meerpohl JJ. Non-nutritive Sweeteners for Diabetes Mellitus. Cochrane Database of Systematic Reviews 2020 May 25;5:CD012885. Doi: 10.1002/14651858.CD012885.pub2