Reconciling conflicting evidence on low- and no-calorie sweeteners and cardiometabolic outcomes: an umbrella review using naïve and bias-adjusted methods.

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.