Low calorie sweeteners and metabolic health: A critical evaluation of the literature

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Science News from the 37th International Symposium on Diabetes and Nutrition

Highlights:

  • Higher quality evidence shows that the intended substitution of sugar calories with low calorie sweeteners can help improve body weight control and associated cardiometabolic risk factors.
  • Current studies establish no clear evidence of adverse effect of low calorie sweeteners on the gut microbiota at doses relevant to human use. The reports of correlated effects stem mainly from animal studies where doses tested are beyond the possible expected intakes of humans.
  • Sweetness liking is part of our human nature. Individuals should be given options such as low calorie sweetened foods or beverages to help them reduce sugars’ intake.

The 37th International Symposium on Diabetes and Nutrition – DNSG 2019, which is the annual meeting of the Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD), took place in Kerkrade, Netherlands, from 12th to 15th June. The Symposium offered three days of exciting discussions among top scientists in the fields of diabetes and nutrition and low calorie sweeteners could not be missing from the agenda. Health organisations globally recommend a reduction of sugars intake for all population groups, which has recently led to a heightened scientific interest in the role of low calorie sweeteners, and of products containing them, in metabolic health.

Reviewing the totality of evidence from human studies

In his talk about low calorie sweeteners and metabolic health, Dr John Sievenpiper, Associate Professor at the University of Toronto in Canada, provided a critical evaluation of the available human research on this topic reviewing outcomes of both clinical controlled trials and of observational studies. When evaluating the impact of low calorie sweeteners on outcomes of metabolic health, findings of randomised controlled trials (RCTs) are largely consistent in showing that use of low calorie sweeteners as a replacement for sugars, particularly in sugar sweetened beverages, could be a helpful strategy to reduce cardiometabolic risk especially among heavy consumers (Malik V, 2019). The intended effects of low calorie sweeteners are expected to differ depending on the energy content of the comparator, and therefore benefits are shown in studies where low calorie sweeteners are used to replace calories from sugars but not when there is no caloric displacement, for example when compared to water or placebo (Sievenpiper et al, 2017).

In contrast to clinical trials, observational studies show mixed and inconsistent results, influenced considerably by methodological issues, which may lead to associations that are at high risk of reverse causality. The use of repeated measures to assess changes in intake and substitution analyses that model the intended replacement strategy for low calorie beverages (i.e., the substitution of low calorie beverages for sugar-sweetened beverages) can somewhat overcome these methodological limitations and provide more consistent, robust, and biologically plausible associations (Khan et al, 2019).

New studies: Benefits with intended substitution of sugar calories with low calorie sweeteners

A new systematic review and meta-analysis of eight randomised controlled trials (RCTs) that was conducted by the department of Nutritional Sciences, Faculty of Medicine, at the University of Toronto and was presented at the 37th International Symposium on Diabetes and Nutrition found that displacement of calories from sugar-sweetened beverages (SSBs) with low calorie sweetened beverages leads to improvement in cardiometabolic risk factors. The analysis showed improvement in body weight, liver fat and diastolic blood pressure with replacement of SSBs with low caloric beverages, and neutral impact on other markers of cardiometabolic risk such as blood lipids and glycaemic response (McGlynn et al, unpublished data presented at DNSG 2019). This finding adds up to results of a recently published study by Malik et al., which found that replacing 1 serving of SSB with 1 serving of low calorie sweetened beverage daily was associated with a 5% lower risk of cardiovascular disease (CVD) mortality and a 4% lower risk of total mortality (Malik et al, 2019). When compared to water, there is no different effect of the consumption of low calorie beverages on body weight and glycaemic control, according to another systematic review and network meta-analysis that was presented as short oral presentation at the conference (McGlynn et al, unpublished data presented at DNSG 2019).

Low calorie sweeteners and gut microbiota: no evidence of effects in humans

In recent years, the role of gut microbiome in human health has gained high research interest. However, when it comes to reported effects of low calorie sweeteners on gut, these stem mainly from animal studies where doses tested are beyond the possible expected intakes of humans. In his talk at the 37th International Symposium on Diabetes and Nutrition, Dr Jotham Suez, post-doctoral fellow at the Weizmann Institute of Science in Israel, presented animal studies published in 2014 that supported that low calorie sweeteners induce glucose intolerance by altering the gut microbiota (Suez et al, 2014). Their results have been criticised in several other works commenting that it is not possible to know whether between-group differences observed in the gut microbiota measures in these mice studies are reflective of changes in diet and/or nutrient and/or fluid intake or changes related to the presence of saccharin, which was anyway delivered in a dose that was far above expected human intakes (Magnuson et al, 2016; Lobach et al, 2019). Importantly, experts stress that there are large differences between the gut microbiome profile in laboratory animals and people, so translating data from animal studies that test effects of extremely high doses of low calorie sweeteners is very suspect.

Presenting their research work in humans, a small clinical experiment in 7 healthy adults who consumed 5 mg/kg/day of saccharin for 1 week, a dose equivalent to the Acceptable Daily Intake (ADI), Dr Suez stated that there is high inter-individuality among humans in relation to their glycaemic response to sweeteners (4 “responders” and 3 “non-responders”) and that differences in the microbiome predict this inter-individuality. However, this small study had numerous and important limitations including the lack of a control group and of controlling for habitual diet , which may be a driving factor behind the reported gut microbial changes that is also supported by the fact that the composition of the gut microbiota of the responder and non-responder groups was already different prior to saccharin consumption. These flaws in design bring into question the biological significance of these reported findings.

Overall, current studies establish no clear evidence of any adverse effect of low calorie sweeteners on the gut microbiota at doses relevant to human use. A recent review concluded that results of metabolism and safety studies show no evidence of a likely mechanism for a clinically relevant effect of low calorie sweeteners on gut microbiota and that normal dietary changes, that have no relationship to low calorie sweeteners, are likely the main reason for changes in the gut microbiota profile (Lobach et al, 2019).

Future directions

In nutrition science, recommendations should be based on the totality of the current evidence and take into consideration their impact on overall diet quality. When it comes to sugar reduction, the balance of current evidence shows that when low calorie sweeteners are used to displace sugar calories, they can be a helpful strategy and bring health benefits attributed to sugar replacement. As sweetness liking is part of the human nature, it is important to provide people with useful tools that could help them reduce their overall sugars intake and low calorie sweeteners can offer such lower/no-sugar options. Finally, the panel of speakers agreed that to address uncertainties, there is a need for more high-quality, large-scale clinical studies and analyses of prospective cohort studies that better manage reverse causality.

  1. Khan TA, Malik VS, Sievenpiper JL. Letter by Khan et al Regarding Article, “Artificially Sweetened Beverages and Stroke, Coronary Heart Disease, and All-Cause Mortality in the Women’s Health Initiative”. Stroke 2019; 50(6): e167-e168
  2. Lobach A, Roberts A, Rowland I. Assessing the in vivo data on low/no-calorie sweeteners and the gut microbiota. Food and Chemical Toxicology 2019; 124: 385-399
  3. Magnuson BA, Carakostas MC, Moore NH, Poulos SP, Renwick AG. Biological fate of low-calorie sweeteners. Nutr. Rev. 2016; 74: 670–689
  4. Malik VS. Non-sugar sweeteners and health. BMJ 2019; 364: k5005. doi: 10.1136/bmj.k5005
  5. Malik VS, Li Y, Pan A, De Koning L, Schernhammer E, Willett WC, et al. Long-term consumption of sugar-sweetened and artificially sweetened beverages and risk of mortality in US adults. Circulation. 2019; 139(18): 2113–2125. doi: 10.1161/CIRCULATIONAHA.118.037401
  6. McGlynn N, Khan TA, Sievenpiper JL. Systematic review and network meta-analysis of non-caloric sweetened beverages versus water and glycemic control. Abstract – Short oral presentation. 37th International Symposium on Diabetes and Nutrition – DNSG 2019
  7. Sievenpiper JL, Khan TA, Ha V, Viguiliouk E, Auyeung R. The importance of study design in the assessment of nonnutritive sweeteners and cardiometabolic health. CMAJ. 2017; 189: E1424–E1425. doi: 10.1503/cmaj.733381
  8. Suez J, Korem T, Zeevi D, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 2014; 514 (7521):181–186.