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

Publication Name: Canadian Medical Association Journal, July 17, 2017 vol. 189 no. 28 E929-E939

Author(s): Azad MB., Abou-Setta AM., Chauhan BF., Rabbani R., Lys J., Copstein L., Mann A., Jeyaraman MM., Reid AE., Fiander M., MacKay DS., McGavock J., Wicklow | Publication Year: 2017


BACKGROUND: Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects.
METHODS: We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points.
RESULTS: From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference ?0.37 kg/m2; 95% confidence interval [CI] ?1.10 to 0.36; I2 9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; I2 0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome.
INTERPRETATION: Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners.


Contrary to the collective evidence from well-designed human trials showing that low calorie sweeteners’ use in place of sugar can help in energy reduction and weight control, this systematic review by Azad et al. claims that low calorie sweeteners might be linked to risk of weight gain and heart disease. The authors draw these conclusions from analysing data of 30 prospective cohort studies, however they miss to clearly acknowledge that although prospective cohort studies have a stronger study design among observational studies, one cannot rule out residual confounding factors and the possibility of reverse causation.

Furthermore, the study supports that evidence from randomised controlled trials (RCTs) does not clearly support the intended benefits of nonnutritive sweeteners for weight management, however, in interpreting the pooled analyses of RCTs, the authors failed to account for the nature of the comparator, as highlighted in a published response to this publication. Importantly, the selection criteria used for the meta-analysis of RCTs in this study led to the exclusion of several well-designed clinical trials that were included in previous thorough systematic reviews and meta-analyses.

The importance of study design in the assessment of nonnutritive sweeteners and cardiometabolic health is highlighted in a response to this new publication by Sievenpiper et al., which concludes: “the conclusion by Azad et al. that the evidence does not support the intended benefits seems unjustified”, and: “Taken together, the available evidence supports the intended benefits of NNS [nonnutritive sweeteners] as being similar to that of other interventions to reduce calories, such as water.” This response can be accessed on the journal’s website by clicking here.

For more information please read the ISA statement by clicking here, and the detailed commentary on this Azad et al. systematic review here.