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

Meghan B. Azad; Ahmed M. Abou-Setta; Bhupendrasinh F. Chauhan; Rasheda Rabbani; Justin Lys; Leslie Copstein; Amrinder Mann; Maya M. Jeyaraman; Ashleigh E. Reid; Michelle Fiander; Dylan S. MacKay; Jon McGavock; Brandy Wicklow; Ryan Zarychanski

doi:10.1503/cmaj.161390

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RE: December 2018 CMAJ cover title for this Research (Synopsis)
Stephen R Workman

Published on: 04 January 2018
Response to: The importance of study design in the assessment of non-nutritive sweeteners and cardiometabolic health
Meghan B. Azad

Published on: 08 September 2017
The timing of ingestion may influence the effect of non-nutritive sweeteners on cardiometabolic health: A potentially overlooked factor
Kei Nakajima1,2

Published on: 07 September 2017
The importance of study design in the assessment of non-nutritive sweeteners and cardiometabolic health
John L. Sievenpiper

Published on: 04 August 2017

Published on: (4 January 2018)

RE: December 2018 CMAJ cover title for this Research (Synopsis)
Stephen R Workman, MD, Dalhousie University
THE SWEET LIFE:What are the effects of sweeteners on our health?
Weight gain was clearly shown. This effect is counterintuitive and easily dismissed.
If the results of the meta analysis of observational studies are proven to be correct the 'f' in 'life' needs to be removed.

Competing Interests: None declared.
Published on: (8 September 2017)

Response to: The importance of study design in the assessment of non-nutritive sweeteners and cardiometabolic health
Meghan B. Azad, PhD
Other Contributors:
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 i...
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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
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Competing Interests: None declared.
Published on: (7 September 2017)

The timing of ingestion may influence the effect of non-nutritive sweeteners on cardiometabolic health: A potentially overlooked factor
Kei Nakajima1,2
Other Contributors:
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 cardiomet...
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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
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Competing Interests: None declared.
Published on: (4 August 2017)

The importance of study design in the assessment of non-nutritive sweeteners and cardiometabolic health
John L. Sievenpiper, MD, PhD, FRCPC
Other Contributors:
Dear Editor,
While we applaud Azad et al. for a comprehensive review of nonnutritive sweeteners (NNS) and ardiometabolic health [1], we are concerned that important methodological considerations were overlooked.
In interpreting the pooled analyses of randomized controlled trials (RCTs), the authors failed to account for the nature of the comparator. One would expect that the intended effect of NNS would differ...
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Dear Editor,
While we applaud Azad et al. for a comprehensive review of nonnutritive sweeteners (NNS) and ardiometabolic health [1], we are concerned that important methodological considerations were overlooked.
In interpreting the pooled analyses of randomized controlled trials (RCTs), the authors failed to account for the nature of the comparator. One would expect that the intended effect of NNS would differ depending on the amount of calories that are available to be displaced from that comparator. As the comparator in the included RCTs was water (4 of 7) [2-5], placebo (2 of 7) [6,7], or a matched weight loss diet (1 of 7) [8], the design did not allow for caloric displacement by NNS. It follows that one would not have expected the NNS in these comparisons to result in any meaningful weight loss or attendant cardiometabolic benefits, an expectation supported by the lack of effect observed in the pooled estimates for body weight, BMI, insulin resistance, and glycosylated hemoglobin [1]. On the other hand, if one focuses on those RCTs in which NNS were used to displace excess calories from sugar-sweetened beverages (SSBs) as the comparator, then the results do favour the intended benefits of NNS. The RCT by Maersk et al [3] was the only eligible RCT to include a direct SSB comparison, a comparison Azad et al. [1] and co-workers elected not to use in their pooled analyses. Although NNS in displacing excess calories from SSBs did not show a significant reduction in body weight change, this comparison did show significant reductions in liver fat, systolic blood pressure, triglycerides, and total cholesterol [3]. Therefore, the conclusion by Azad et al. [1] that the evidence does not support the intended benefits seems unjustified.
The authors also accorded too much weight to prospective cohort studies in their conclusions. Although prospective cohort studies offer the best protection against bias among observational studies, based on their long longitudinal follow-up, ability to adjust for multiple confounding factors, and ascertainment of clinical outcomes rather than surrogate biomarkers, one cannot rule out residual confounding in these studies. In particular, it is well documented that prospective cohort studies of NNS are at a high risk of reverse causality, as higher consumers of NNS may choose these products because they are at a higher risk for adverse cardiometabolic outcomes and not the other way around [9]. The prospective design of these studies does not necessarily limit this type of confounding, despite the authors'" claims to the contrary. The evidence presented by the authors' is also subject to other important limitations including publication bias (diabetes); inconsistency (diabetes and hypertension); indirectness (hypertension, stroke, coronary heart disease and cardiovascular disease); and imprecision in the pooled estimates (diabetes, hypertension, stroke and coronary heart disease). These uncertainties suggest that the current estimates from prospective cohort studies are not trustworthy and new research is likely to have an important impact on their direction, magnitude, and precision.
Taken together, the available evidence supports the intended benefits of NNS as being similar to that of other interventions to reduce calories, such as water. Although prospective cohort studies have shown an adverse association with incident hypertension, stroke, and cardiovascular disease, these associations are discordant with the higher quality evidence from RCTs and are at high risk of reverse causality, among other important limitations. To improve the estimates, we agree that there is a need for more long-term randomized trials of interventions using NNS to reduce excess calories from sugars, especially from SSBs.
References
1. 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:E929-E39. 2.Tate DF, Turner-McGrievy G, Lyons E, et al. Replacing caloric beverages with water or diet beverages for weight loss in adults: main results of the Choose Healthy Options Consciously Everyday (CHOICE) randomized clinical trial. The American journal of clinical nutrition. 2012;95:555-63. 3. Maersk M, Belza A, Stodkilde-Jorgensen H, et al. Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: a 6-mo randomized intervention study. The American journal of clinical nutrition. 2012;95:283-9. 4. Madjd A, Taylor MA, Delavari A, Malekzadeh R, Macdonald IA, Farshchi HR. Effects on weight loss in adults of replacing diet beverages with water during a hypoenergetic diet: a randomized, 24-wk clinical trial. The American journal of clinical nutrition. 2015;102:1305-12. 5. Peters JC, Beck J, Cardel M, et al. The effects of water and non-nutritive sweetened beverages on weight loss and weight maintenance: A randomized clinical trial. Obesity. 2016;24:297-304. 6. Hsieh MH, Chan P, Sue YM, et al. Efficacy and tolerability of oral stevioside in patients with mild essential hypertension: a two-year, randomized, placebocontrolled study. Clin Ther 2003;25:2797-808 7. Ferri LA, Alves-Do-Prado W, Yamada SS, et al. Investigation of the antihypertensive efect of oral crude stevioside in patients with mild essential hypertension. Phytother Res 2006;20:732-6. 8. Blackburn GL, Kanders BS, Lavin PT, Keller SD, Whatley J. The effect of aspartame as part of a multidisciplinary weight-control program on short-and long-term control of body weight. The American journal of clinical nutrition. 1997;65:409-18. 9. Dietary Guidelines Advisory Committee. 2015-2020 Dietary Guidelines for Americans - health.gov2015.
Conflict of Interest:
Dr. Tauseef A Khan has received research support from the Canadian Institutes of health Research (CIHR) and an unrestricted travel donation from Bee Maid Honey Ltd. Vanessa Ha has received research support from World Health Organization (WHO). She has received a travel award and doctoral scholarship from CIHR. Effie Viguiliouk and Rodney Auyeung do not declare any competing interests. Dr. John L Sievenpiper has received research support from the CIHR, Canadian Diabetes Association (CDA), PSI Foundation, Banting and Best Diabetes Centre (BBDC), Canadian Nutrition Society (CNS), American Society for Nutrition (ASN), Calorie Control Council, INC International Nut and Dried Fruit Council Foundation, National Dried Fruit Trade Association, The Tate and Lyle Nutritional Research Fund at the University of Toronto, and The Glycemic Control and Cardiovascular Disease in Type 2 Diabetes Fund at the University of Toronto (a fund established by the Alberta Pulse Growers). He has received speaker fees and/or honoraria from the CDA, CNS, Dr. Pepper Snapple Group, Dairy Farmers of Canada, Nutrition Foundation of Italy (NFI), C3 Collaborating for Health, Sprim Brasil, WhiteWave Foods, Rippe Lifestyle, mdBriefcase, Alberta Milk, FoodMinds LLC, Memac Ogilvy & Mather LLC, PepsiCo, The Ginger Network LLC, International Sweeteners Association, and Pulse Canada. He has ad hoc consulting arrangements with Winston & Strawn LLP, Perkins Coie LLP, and Tate & Lyle. He is a member of the European Fruit Juice Association Scientific Expert Panel. He is on the Clinical Practice Guidelines Expert Committees of the CDA, European Association for the study of Diabetes (EASD), and Canadian Cardiovascular Society (CCS), as well as an expert writing panel of the ASN. He serves as an unpaid scientific advisor for the Food, Nutrition, and Safety Program (FNSP) and the Technical Committee on Carbohydrates of the International Life Science Institute (ILSI) North America. He is a member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the EASD, and Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. His wife is an employee of Unilever Canada.
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Competing Interests: None declared.