Abstract
Inconsistency among evidence syntheses has led to opposing guidelines and public confusion regarding low- and no-calorie sweeteners (LNCS) in noncommunicable diseases. To understand the role of different analytical approaches in assessing LNCS and cardiometabolic outcomes, we conducted an umbrella review of systematic reviews and meta-analyses. MEDLINE, EMBASE, and Cochrane were searched for systematic reviews and meta-analyses of trials or cohorts that had at least two analytical approaches: naïve (LNCS vs. all-comparators (trials) and prevalent (cohorts)) and bias-adjusted (LNCS vs. intended or reference substitution (trials) and LNCS change or intended or reference substitution (cohorts)). Grading of Recommendations Assessment, Development, and Evaluation assessed certainty of evidence. We included six trial- and five cohort-based analyses. In trials, LNCS reduced energy, body weight, and body fat in both analyses and body mass index and systolic blood pressure in bias-adjusted only, while glycosylated hemoglobin showed smaller reductions than water in bias-adjusted only. In analyses of cohorts, LNCS was associated with higher obesity, diabetes, stroke, and cardiovascular and all-cause mortality in naïve analyses but lower body weight, waist circumference, obesity, coronary heart disease, and cardiovascular and all-cause mortality in bias-adjusted analyses. The certainty of evidence was generally moderate for trials and very low for cohorts. LNCS show benefits across analytical approaches in both analyses of trials. These results agree with bias-adjusted analyses of cohorts, in which LNCS are associated benefits across cardiometabolic outcomes, but not naïve analyses of cohorts. Systematic reviews and meta-analyses using bias-reduction methods support the use of LNCS as a sugar-reduction strategy. Protocol registration: https://doi.org/10.17605/OSF.IO/TSEQM.
Summary
The umbrella review by Ayoub-Charette et al. revealed a significant methodological divide: while “naïve” analyses of cohort studies with prevalent dietary assessment often associate LNCS with increased risks of obesity, diabetes, and other chronic disease, “bias-adjusted” analyses that more accurately model the intended substitution of LNCS for sugar showed the opposite, aligning with clinical trial data. Specifically, when LNCS were used to replace sugar and reduce overall calories, they were consistently associated with reductions in body weight, body fat, and energy intake in RCTs, and with lower body weight and obesity, coronary heart disease, cardiovascular and all-cause mortality in “bias-adjusted” cohort analyses. These results suggest that the perceived health risks found in some observational studies may be due to methodological flaws like reverse causality rather than LNCS themselves.