Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies

Dear Editor,

We thank Sievenpiper et al. for their interest in our work. While we agree that study design must be considered when evaluating evidence to inform health decision making, it is often necessary to look beyond randomized controlled trials (RCTs) for additional (and sometimes more appropriate) evidence. Despite their strengths, RCTs can have substantial limitations including insufficient duration of intervention or follow-up, small sample size / low power, poor external validity due to enrollment of a highly selected population, reliance on imperfect surrogate outcomes, and inability to reliably estimate safety outcomes [1]. Reflecting these potential weaknesses, the RCTs eligible for our meta-analysis [2] collectively enrolled only 1003 individuals who were followed for a median of 6 months. Participants were overweight or had hypertension, and the trials focused on short term changes in body composition rather than cardiovascular disease.

We have acknowledged and discussed the limitations of observational studies, and clearly articulated that despite relatively consistent results across multiple large prospective cohort studies (405,907 individuals followed for a median of 10 years), most observed associations have not been confirmed in RCTs. However, RCTs published to date have not evaluated the long-term impact of non-nutritive sweeteners (NNS) on cardiometabolic outcomes such as type 2 diabetes, hypertension and cardiovascular disease. This is not surprising, as it would be extremely costly and challenging to enroll a sufficient number of participants, achieve adherence to a long-term dietary intervention, and conduct sufficiently long-term follow-up to evaluate these relatively uncommon outcomes that progress slowly over time. Large prospective cohort studies address these challenges and offer a powerful opportunity to pose research questions that cannot be feasibly addressed in RCTs.

We agree that it is important to consider the nature of the comparator in RCTs, and that NNS trials using caloric comparators are useful to evaluate the replacement of sugar with NNS. This is particularly relevant to short-term strategies to reduce sugar intake and lose weight; however, we explicitly aimed to evaluate the long term effects of routine NNS consumption - a pattern that is increasingly common in the general population, with 40% of adults and 25% of children reporting regular NNS consumption [3]. In this scenario, rather than "replacing sugar", individuals are consuming NNS as a regular component of their habitual diet and thus, "no NNS" (placebo or non-caloric comparator) is a more relevant control.

We disagree with the statement that "the available evidence supports the intended benefits of NNS as being similar to that of other interventions to reduce calories, such as water". While evidence from RCTs suggests equivalence to water or other non-caloric comparators for relatively short-term outcomes, evidence from prospective observational studies suggests potentially adverse long-term associations with incident hypertension, stroke and cardiovascular disease. These observational data are not "discordant" with evidence from RCTs because no RCTs to date have reported on these outcomes. In the absence of long-term cardiovascular and safety data, claiming that NNS are analogous to water is unjustified and potentially irresponsible. The absence of short-term adverse effects from RCTs does not establish long-term safety.

We fully agree that further research is needed to clarify the long- term effects of NNS - both synthetic and 'natural', evaluated against caloric and non-caloric comparators. Multiple study designs and diverse data sources will be required to address these questions, and in all cases, it will be important to consider study sponsorship and author conflicts of interest as potential sources of bias [4]. To this end, we are pleased that the Canadian Institutes of Health Research have recognized this important knowledge gap and dedicated public funds to support research on NNS as part of their recent "Sugar & Health" strategic funding opportunity. We look forward to the results of this and other research to establish the long-term risks and benefits of NNS.

References

1. Frieden TR. Evidence for Health Decision Making - Beyond Randomized, Controlled Trials. The New England Journal of Medicine 2017;377(5):465-475.

2. 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.

3. Sylvetsky AC, Jin Y, Clark EJ, Welsh JA, Rother KI, Talegawkar SA. Consumption of Low-Calorie Sweeteners among Children and Adults in the United States. Journal of the Academy of Nutrition and Dietetics 2017;117(3):441-448 e442.

4. Mandrioli D, Kearns CE, Bero LA. Relationship between Research Outcomes and Risk of Bias, Study Sponsorship, and Author Financial Conflicts of Interest in Reviews of the Effects of Artificially Sweetened Beverages on Weight Outcomes: A Systematic Review of Reviews. PLoS One 2016;11(9):e0162198.

Conflict of Interest:

None declared

Dear Editor,

We appreciate the recent review for nonnutritive sweeteners (NNS) by Azad et al. [1]. We agree with the updated important comments by Sievenpiper et al. [2], who pointed out the issue of comparators in randomized, controlled trials, and the high risk of potential bias and reverse causality in prospective cohort studies. However, other overlooked factors may also influence the effect of NNS on cardiometabolic risks. When NNS is consumed in the fasting state, but not in the post-prandial state, NNS more likely affects the gut membrane and receptors in the gut. NNS might stimulate secretion of incretins [3,4], which can prevent overeating and occasionally lead to anorexia. Furthermore, dissociation between sweet taste and energy or plasma glucose may occur [5,6]. Hypoglycemia could occur in the condition of long-term fasting, possibly with the concomitant effect of incretins. We consider that the mechanisms of hypoglycemia, increased consumption of food, and obesity may contribute, at least partly, to the conflicting and unexpected results of many clinical studies.

In the post-prandial state, possible interference of NNS with extraoral receptors and potential consequent adverse effects, including hypoglycemia, could be attenuated. This is because extraoral receptors are more likely to be occupied with substances in foods and a large amount of food may simultaneously keep NNS from contacting the mucous membrane of the gut. Moreover, because plasma glucose levels increase after regular meals, the dissociation mentioned above is unlikely to occur. Further clinical studies considering these issues are required to investigate the potential benefits or adverse effects of consumption of NNS.

Kei Nakajima, MD, PhD,1,2

Taizo Iwane, RD, 1 PhD,

Ryoko Higuchi, RD 1

1 School of Nutrition and Dietetics, Faculty of Health and Social Services, Kanagawa University of Human Services, 1-10-1 Heisei-cho, Yokosuka, Kanagawa, 238-8522, Japan.

2 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan.

References 1. Azad MB, Abou-Setta AM, Chauhan BF, Rabbani R, Lys J, Copstein 2, Mann A, Jeyaraman MM, Reid AE, Fiander M, MacKay DS, McGavock J, Wicklow B, Zarychanski R. Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. CMAJ. 2017;189:E929-E939. 2. Sievenpiper JL, Khan TA, Ha V, Viguiliouk E, Auyeung R. The importance of study design in the assessment of non-nutritive sweeteners and cardiometabolic health. CMAJ published online August 4, 2017 3. Brown RJ, Rother KI. Non-nutritive sweeteners and their role in the gastrointestinal tract. J Clin Endocrinol Metab. 2012;97:2597-2605. 4. Chan CB, Hashemi Z, Subhan FB. The impact of low and no-caloric sweeteners on glucose absorption, incretin secretion, and glucose tolerance. Appl Physiol Nutr Metab. 2017;42:793-801. 5. Pepino MY, Bourne C. Non-nutritive sweeteners, energy balance, and glucose homeostasis. Curr Opin Clin Nutr Metab Care. 2011;14:391-395. 6. Romo-Romo A, Aguilar-Salinas CA, Gomez-Diaz RA, Brito-Cordova GX, Gomez-Velasco DV, Lopez-Rocha MJ, Almeda-Valdes P. Non-Nutritive Sweeteners: Evidence on their Association with Metabolic Diseases and Potential Effects on Glucose Metabolism and Appetite. Rev Invest Clin. 2017;69:129-138.

Conflict of Interest:

None declared