Background: There has been an emerging concern that non-nutritive sweeteners (NNS) can increase the risk of cardiometabolic disease. Much of the attention has focused on acute metabolic and endocrine responses to NNS. To examine whether these mechanisms are operational under real-world scenarios, we conducted a systematic review and network meta-analysis of acute trials comparing the effects of non-nutritive sweetened beverages (NNS beverages) with water and sugar-sweetened beverages (SSBs) in humans. Methods: MEDLINE, EMBASE, and The Cochrane Library were searched through to January 15, 2022. We included acute, single-exposure, randomized, and non-randomized, clinical trials in humans, regardless of health status. Three patterns of intake were examined: (1) uncoupling interventions, where NNS beverages were consumed alone without added energy or nutrients; (2) coupling interventions, where NNS beverages were consumed together with added energy and nutrients as carbohydrates; and (3) delayed coupling interventions, where NNS beverages were consumed as a preload prior to added energy and nutrients as carbohydrates. The primary outcome was a 2 h incremental area under the curve (iAUC) for blood glucose concentration. Secondary outcomes included 2 h iAUC for insulin, glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), peptide YY (PYY), ghrelin, leptin, and glucagon concentrations. Network meta-analysis and confidence in the network meta-analysis (CINeMA) were conducted in R-studio and CINeMA, respectively. Results: Thirty-six trials involving 472 predominantly healthy participants were included. Trials examined a variety of single NNS (acesulfame potassium, aspartame, cyclamate, saccharin, stevia, and sucralose) and NNS blends (acesulfame potassium + aspartame, acesulfame potassium + sucralose, acesulfame potassium + aspartame + cyclamate, and acesulfame potassium + aspartame + sucralose), along with matched water/unsweetened controls and SSBs sweetened with various caloric sugars (glucose, sucrose, and fructose). In uncoupling interventions, NNS beverages (single or blends) had no effect on postprandial glucose, insulin, GLP-1, GIP, PYY, ghrelin, and glucagon responses similar to water controls (generally, low to moderate confidence), whereas SSBs sweetened with caloric sugars (glucose and sucrose) increased postprandial glucose, insulin, GLP-1, and GIP responses with no differences in postprandial ghrelin and glucagon responses (generally, low to moderate confidence). In coupling and delayed coupling interventions, NNS beverages had no postprandial glucose and endocrine effects similar to controls (generally, low to moderate confidence). Conclusions: The available evidence suggests that NNS beverages sweetened with single or blends of NNS have no acute metabolic and endocrine effects, similar to water. These findings provide support for NNS beverages as an alternative replacement strategy for SSBs in the acute postprandial setting.

The World Health Organization’s (WHO) Nutrition and Food Safety Department recently released a guideline on the use of non-sugar sweeteners (NSS) [1] based upon the analysis of a WHO-commissioned systematic review and meta-analysis (SRMA) [2]. The guideline mentions that NSS use in randomized controlled trials (abbreviated as trials) showed a reduction in adiposity outcomes but in prospective cohort studies, NSS intake was associated with increased adiposity and chronic disease risk. Despite conflicting results between the study types, the WHO’s recommendation is very specific: "NSS not be used as a means of achieving weight control or reducing the risk of non-communicable diseases (conditional recommendation)”. We have two major concerns with the WHO guideline, limiting its usefulness, and call for a re-evaluation of the results and recommendation.

BACKGROUND:Health authorities are near universal in their recommendation to replace sugar-sweetened beverages (SSBs) with water. Non-nutritive sweetened beverages (NSBs) are not as widely recommended as a replacement strategy due to a lack of established benefits and concerns they may induce glucose intolerance through changes in the gut microbiome. The STOP Sugars NOW trial aims to assess the effect of the substitution of NSBs (the "intended substitution") versus water (the "standard of care substitution") for SSBs on glucose tolerance and microbiota diversity. DESIGN AND METHODS:The STOP Sugars NOW trial (NCT03543644) is a pragmatic, "head-to-head", open-label, crossover, randomized controlled trial conducted in an outpatient setting. Participants were overweight or obese adults with a high waist circumference who regularly consumed ≥1 SSBs daily. Each participant completed three 4-week treatment phases (usual SSBs, matched NSBs, or water) in random order, which were separated by ≥4-week washout. Blocked randomization was performed centrally by computer with allocation concealment. Outcome assessment was blinded; however, blinding of participants and trial personnel was not possible. The two primary outcomes are oral glucose tolerance (incremental area under the curve) and gut microbiota beta-diversity (weighted UniFrac distance). Secondary outcomes include related markers of adiposity and glucose and insulin regulation. Adherence was assessed by objective biomarkers of added sugars and non-nutritive sweeteners and self-report intake. A subset of participants was included in an Ectopic Fat sub-study in which the primary outcome is intrahepatocellular lipid (IHCL) by 1H-MRS. Analyses will be according to the intention to treat principle. BASELINE RESULTS:Recruitment began on 1 June 2018, and the last participant completed the trial on 15 October 2020. We screened 1086 participants, of whom 80 were enrolled and randomized in the main trial and 32 of these were enrolled and randomized in the Ectopic Fat sub-study. The participants were predominantly middle-aged (mean age 41.8 ± SD 13.0 y) and had obesity (BMI of 33.7 ± 6.8 kg/m2) with a near equal ratio of female: male (51%:49%). The average baseline SSB intake was 1.9 servings/day. SSBs were replaced with matched NSB brands, sweetened with either a blend of aspartame and acesulfame-potassium (95%) or sucralose (5%). CONCLUSIONS:Baseline characteristics for both the main and Ectopic Fat sub-study meet our inclusion criteria and represent a group with overweight or obesity, with characteristics putting them at risk for type 2 diabetes. Findings will be published in peer-reviewed open-access medical journals and provide high-level evidence to inform clinical practice guidelines and public health policy for the use NSBs in sugars reduction strategies. TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT03543644.

Background: Adverse associations of low-and no-calorie sweetened beverages (LNCSBs) with cardiometabolic outcomes in observational studies may be explained by reverse causality and residual confounding. Purpose: To address these limitations we used change analyses of repeated measures of intake and substitution analyses to synthesize the association of LNCSBs with cardiometabolic outcomes. Study Selection: MEDLINE, EMBASE, and the Cochrane Library were searched up to 10 June 2021 for prospective cohort studies ≥1-year follow-up duration in adults. Outcomes included changes in clinical measures of adiposity, risk of overweight/obesity, metabolic syndrome, diabetes, cardiovascular disease, and total mortality. Data Extraction: Two independent reviewers extracted data, assessed study quality, and certainty of evidence using GRADE. Data was pooled using random-effects model and expressed as mean difference (MD) or risk ratio (RR) and 95% CI. Data Synthesis: Fourteen cohorts (416,830 participants) met the eligibility criteria. Change in LNCSB intake was associated with lower weight (5 cohorts, 136,206 participants; MD, -0.008 [95% CI: -0.014, -0.002] kg/y). Substitution of LNCSBs for sugar-sweetened beverages (SSBs) was associated with lower weight (3 cohorts, 165,579 participants; MD, -0.12 [95% CI: -0.14, -0.01] kg/y) and lower incidence of obesity (1 cohort, 15,765 participants; RR, 0.88 [0.88, 0.89]), coronary heart disease (6 cohorts, 233,676 participants; RR, 0.89 [95% CI: 0.81, 0.98]), CVD mortality (1 cohort, 118,363 participants; RR, 0.95 [95% CI: 0.90, 0.99]), and total mortality (1 cohort, 118,363 participants; RR, 0.96 [95% CI: 0.94, 0.98]) with no adverse associations across other outcomes. Substitution of water for SSBs showed lower weight (3 cohorts, 165,579 participants; MD, -0.10 [95% CI: -0.13, -0.06] kg/y), lower waist circumference (1 cohort, 173 participants; MD, -2.71[95% CI: -4.27, -1.15] cm/y) and percent body fat (1 cohort, 173 participants; MD, -1.51 [95% CI: -2.61, -0.42] %/y), and lower incidence of obesity (1 cohort, 15,765 participants; RR, 0.85 [95% CI: 0.75, 0.97]) and diabetes (3 cohorts, 281,855 participants; RR, 0.96 [95% CI: 95% CI: 0.94, 0.98]). Substitution of LNCSBs for water showed no adverse associations. Limitations: The evidence was low to very low certainty owing downgrades for imprecision, indirectness and/or inconsistency. Conclusions: LNCSBs were not associated with cardiometabolic harm in analyses that model the exposure as change or substitutions. The available evidence provides some indication that LNCSBs in their intended substitution for SSBs may be associated with cardiometabolic benefit, comparable to the standard of care, water.

Preoperative carbohydrate beverages have been shown to be beneficial in improving patient outcomes. There have been several investigations into the safety of maltodextrin as a preoperative carbohydrate. Although alternative preoperative carbohydrate sources have been proposed, there have been few investigations into the safety and gastric emptying of novel carbohydrate beverages. The present study aimed to compare the gastric emptying of phytoglycogen and maltodextrin to evaluate safety for use as presurgical carbohydrate beverages. In a quasi-experimental design, ten healthy participants orally consumed either a 12.5% maltodextrin or a 12.5% phytoglycogen solution. Gamma scintigraphy was used to evaluate gastric emptying at baseline at 45, 90, and 120 min. Serum insulin and serum glucose were measured at baseline at 15, 30, 45, 60, 90, and 120 min. Gastric volume was significantly lower in the phytoglycogen group at 45 min (p = 0.01) and 90 min (p = 0.01), but this difference lost significance at 120 min (p = 0.17). There were no significant differences between treatments for serum insulin or serum glucose at any time point. This study indicates that the gastric emptying of phytoglycogen is comparable to maltodextrin at 120 min after ingestion, opening the opportunity for the study of alternative carbohydrates for utilization as preoperative carbohydrates.

IMPORTANCE There are concerns that low- and no-calorie sweetened beverages (LNCSBs) do not have established benefits, with major dietary guidelines recommending the use of water and not LNCSBs to replace sugar-sweetened beverages (SSBs). Whether LNCSB as a substitute can yield similar improvements in cardiometabolic risk factors vs water in their intended substitution for SSBs is unclear. OBJECTIVE To assess the association of LNCSBs (using 3 prespecified substitutions of LNCSBs for SSBs, water for SSBs, and LNCSBs for water) with body weight and cardiometabolic risk factors in adults with and without diabetes. DATA SOURCES Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception through December 26, 2021. STUDY SELECTION Randomized clinical trials (RCTs) with at least 2 weeks of interventions comparing LNCSBs, SSBs, and/or water were included. DATA EXTRACTION AND SYNTHESIS Data were extracted and risk of bias was assessed by 2 independent reviewers. A network meta-analysis was performed with data expressed as mean difference (MD) or standardized mean difference (SMD) with 95% CIs. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to assess the certainty of the evidence. MAIN OUTCOMES AND MEASURES The primary outcome was body weight. Secondary outcomes were other measures of adiposity, glycemic control, blood lipids, blood pressure, measures of nonalcoholic fatty liver disease, and uric acid. RESULTS A total of 17 RCTs with 24 trial comparisons were included, involving 1733 adults (mean [SD] age, 33.1 [6.6] years; 1341 women [77.4%]) with overweight or obesity who were at risk for or had diabetes. Overall, LNCSBs were a substitute for SSBs in 12 RCTs (n = 601 participants), water was a substitute for SSBs in 3 RCTs (n = 429), and LNCSBs were a substitute for water in 9 RCTs (n = 974). Substitution of LNCSBs for SSBs was associated with reduced body weight (MD, -1.06 kg; 95% CI, -1.71 to -0.41 kg), body mass index (MD, -0.32; 95% CI, -0.58 to -0.07), percentage of body fat (MD, -0.60%; 95% CI, -1.03% to -0.18%), and intrahepatocellular lipid (SMD, -0.42; 95% CI, -0.70 to -0.14). Substituting water for SSBs was not associated with any outcome. There was also no association found between substituting LNCSBs for water with any outcome except glycated hemoglobin A(1c) (MD, 0.21%; 95% CI, 0.02% to 0.40%) and systolic blood pressure (MD, -2.63 mm Hg; 95% CI, -4.71 to -0.55 mm Hg). The certainty of the evidence was moderate (substitution of LNCSBs for SSBs) and low (substitutions of water for SSBs and LNCSBs for water) for body weight and was generally moderate for all other outcomes across all substitutions. CONCLUSIONS AND RELEVANCE This systematic review and meta-analysis found that using LNCSBs as an intended substitute for SSBs was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm and had a similar direction of benefit as water substitution. The evidence supports the use of LNCSBs as an alternative replacement strategy for SSBs over the moderate term in adults with overweight or obesity who are at risk for or have diabetes.

Health authorities recommend reducing added or free sugars to ≤5–10% energy. Much attention has focussed of the reduction of SSBs with the recommendation that SSBs be replaced with unsweetened healthy alternatives such as water but not non-nutritive sweetened beverages (NSBs). There are concerns that non-nutritive sweeteners do not have the intended benefits and may induce glucose intolerance through changes in the gut microbiome. Whether NSBs have benefits similar to water in their intended substitution for SSBs is unclear. To address this question, we have undertaken the STOP Sugars NOW trial (NCT03543644), a pragmatic “head-to-head” crossover randomized controlled trial of the effect of NSBs (the intended substitution) versus water (the standard of care) as a replacement strategy for SSBs on glucose tolerance and gut microbiome diversity. We recruited overweight or obese participants with a high waist circumference who regularly consume ≥1 SSBs/day. Each participant underwent a ≥2-week run-in period followed by three 4- week treatment phases in random order (usual SSBs, equivalent NSBs, or water) with each phase separated by a ≥4-week washout. The two primary outcomes are change in glucose tolerance and gut microbiome beta- diversity. Adherence to the interventions will be assessed by objective biomarkers of added sugars (13C/12C isotopic ratio in serum fatty acids and urinary fructose and sucrose) and non-nutritive sweeteners (urinary sucralose and acesulfame-potassium). The trial started on June 1st, 2018 with the first participant undergoing randomization on August 1st, 2019 and the last participant finishing on October 15th, 2020. We screened 1,086 individuals, out of which 80 were randomized. Baseline characteristics showed a mean age of 41.8 ± 13.0 y, BMI of 33.7 ± 6.8 kg/m2, waist circumference of 108.7 ± 13.5 cm, and mean SSBs intake of 2 SSBs/day. The results of this trial will directly inform public health guidance on the use of NSBs in sugars reduction strategies. CIHR.

Sugar-sweetened beverages (SSBs) have been linked to weight gain, and it is unclear if other food sources of fructose-containing sugars behave similarily. We conducted a systematic review and meta-analysis of controlled feeding trials to assess the effect of different food sources of fructose-containing sugars on body weight. MEDLINE, EMBASE, and The Cochrane library were searched through January 2019. We included controlled feeding trials of ≥2 weeks investigating the effect of different food sources of sugars. Four levels of energy control were prespecified: substitution (energy-matched comparisons); addition (energy from sugars added to diet); subtraction (energy from sugars subtracted from diet); or ad libitum (energy from sugars freely replaced). The primary outcome was body weight. Two independent reviewers extracted data and assessed risk of bias. Data were pooled using random effects models and expressed as mean differences (MDs) with 95% confidence intervals (CIs). GRADE assessed the certainty of evidence. We identified 110 controlled trials (N = 5133) assessing the effect of 7 different food sources of fructose-containing sugars (SSBs, fruit, fruit juice, dried fruit; baked goods, sweets, & desserts; mixed sources; added caloric sweeteners). No effect on body weight was observed in substitution trials, whereas there was an increasing effect in addition trials (MD, 0.23 kg [95% CI, 0.06 to 0.40]) and ad libitum trials (1.43 kg [0.78 to 2.16]), and a decreasing effect in subtraction trials (–0.52 kg [–1.02 to −0.02]). There was evidence of interaction by food source with fruit showing weight loss in substitution trials and SSBs showing weight gain in addition trials. The certainty of evidence was moderate for the effects in the addition and subtraction trials and high for the effects in the substitution and ad libitum trials. Energy control and food source appear to mediate the effect of fructose-containing sugars on body weight. Food sources of fructose-containing sugars adding excess energy to diets (especially sugars-sweetened beverages) appear to lead to weight gain. There is low to moderate likelihood that more research will substantially alter our estimates (ClinicalTrials.gov Identifier, NCT02558920) American Society for Nutrition Foundation (commissioned and funded), Diabetes Canada.

Concerns exist that NSBs do not have established benefits, with major dietary guidelines recommending that water and not NSBs replace sugar-sweetened beverages (SSBs). Whether NSBs improve cardiometabolic risk factors similar to water in their intended substitution for SSBs is unclear. To inform the update of the European Association for the Study of Diabetes (EASD) clinical practice guidelines for nutrition therapy, we conducted a systematic review and network meta-analysis to assess the effect of substituting NSBs for SSBs, water for SSBs and NSBs for water on cardiometabolic risk factors in people with and without diabetes. We searched MEDLINE, Embase and the Cochrane Library through March 2019. Randomized controlled trials (RCTs) ≥ 1 week comparing NSBs, SSBs, and/or water were included. Outcomes were measures of adiposity, glycemic control, lipids, blood pressure, nonalcoholic fatty liver disease and uric acid. Two independent reviewers extracted data and assessed risk of bias. A frequentist network meta-analysis was performed for the substitution of NSBs for SSBs, water for SSBs and NSBs for water. Data were expressed as mean (MD) or standardized mean (SMD) differences with 95% confidence intervals (CI). GRADE assessed certainty of evidence. We identified 14 RCTs (n = 1530) substituting NSBs for SSBs (7 trials, N = 483), NSBs for water (7 trials, n = 852) and water for SSBs (2 trials, n = 285) mostly in people at risk for or with diabetes. Substitution of NSBs for SSBs reduced body weight (MD, −1.11 kg [95% CI, −1.90 to –0.32]), BMI (−0.32 kg/m2 [−0.58 to –0.07]), body fat (−0.60% [−1.03 to –0.18]), triglycerides (−0.24 mmol/L [−0.45 to −0.02]), and liver fat (SMD, −0.44 [95% CI, −0.69 to –0.19]). Substitution of water for SSBs reduced only uric acid (–0.05 mmol/L [–0.08 to −0.01]). There was no effect of substituting NSBs for water on any outcome except HbA1c (0.21% [0.02 to 0.40]). The certainty of the evidence ranged from low to high. The intended substitution of NSBs for SSBs improves cardiometabolic risk factors, showing similar benefits to water. The available evidence supports the use of NSBs as an alternative replacement strategy for SSBs. There is a need for more high-quality RCTs. (ClinicalTrials.gov identifier, NCT02879500) Diabetes and Nutrition Study Group of the EASD, CIHR, Diabetes Canada.