Background: Fructose providing excess calories in the form of sugar sweetened beverages (SSBs) increases markers of non-alcoholic fatty liver disease (NAFLD). Whether this effect holds for other important food sources of fructose-containing sugars is unclear. To investigate the role of food source and energy, we conducted a systematic review and meta-analysis of controlled trials of the effect of fructose-containing sugars by food source at different levels of energy control on non-alcoholic fatty liver disease (NAFLD) markers. Methods and Findings: MEDLINE, Embase, and the Cochrane Library were searched through 7 January 2022 for controlled trials ≥7-days. Four trial designs were prespecified: substitution (energy-matched substitution of sugars for other macronutrients); addition (excess energy from sugars added to diets); subtraction (excess energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced by other macronutrients). The primary outcome was intrahepatocellular lipid (IHCL). Secondary outcomes were alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Independent reviewers extracted data and assessed risk of bias. The certainty of evidence was assessed using GRADE. We included 51 trials (75 trial comparisons, n = 2059) of 10 food sources (sugar-sweetened beverages (SSBs); sweetened dairy alternative; 100% fruit juice; fruit; dried fruit; mixed fruit sources; sweets and desserts; added nutritive sweetener; honey; and mixed sources (with SSBs)) in predominantly healthy mixed weight or overweight/obese younger adults. Total fructose-containing sugars increased IHCL (standardized mean difference = 1.72 [95% CI, 1.08 to 2.36], p < 0.001) in addition trials and decreased AST in subtraction trials with no effect on any outcome in substitution or ad libitum trials. There was evidence of influence by food source with SSBs increasing IHCL and ALT in addition trials and mixed sources (with SSBs) decreasing AST in subtraction trials. The certainty of evidence was high for the effect on IHCL and moderate for the effect on ALT for SSBs in addition trials, low for the effect on AST for the removal of energy from mixed sources (with SSBs) in subtraction trials, and generally low to moderate for all other comparisons. Conclusions: Energy control and food source appear to mediate the effect of fructose-containing sugars on NAFLD markers. The evidence provides a good indication that the addition of excess energy from SSBs leads to large increases in liver fat and small important increases in ALT while there is less of an indication that the removal of energy from mixed sources (with SSBs) leads to moderate reductions in AST. Varying uncertainty remains for the lack of effect of other important food sources of fructose-containing sugars at different levels of energy control.

Use of health applications (apps) to support healthy lifestyles has intensified. Different app features may support effectiveness, including gamification defined as the use of game elements in a non-game situation. Whether health apps with gamification can impact behaviour change and cardiometabolic risk factors remains unknown. We conducted a systematic review and meta-analysis to determine the effect of health apps with gamification compared to non-gamified apps (control) on physical activity and cardiometabolic risk factors. MEDLINE, EMBASE, and Cochrane library databases were searched through May 21st, 2024. We included controlled trials in adults (≥1 years) of all health backgrounds, with intervention periods ≥8-weeks, assessing the effect of gamification strategies used in health behaviour apps on adherence, cardiometabolic risk factors, total energy, and dietary nutrients of concern. Independent reviewers extracted relevant data and assessed risk of bias. Outcomes included physical activity and cardiometabolic risk factors (adiposity, glycemia, lipids, blood pressure and dietary factors). Data were pooled using the inverse variance method and expressed as mean differences (MD) with 95% confidence intervals (CI). Certainty of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Protocol registration was on ClinicalTrials.gov (NCT04633070). 36 trials (49 trial comparisons, n = 10,079) met eligibility criteria; most targeted physical activity or weight loss. Use of gamification in apps compared to non-gamified interventions resulted in trivial increases in steps (489 steps/day [64 to 914]; high), and reductions in body mass index (-0.28 kg/m² [-0.44 to -0.12]; moderate) and body weight (-0.70 kg [-1.18 to -0.22]; moderate), and small important reductions in body fat (-1.92% [-2.71 to -1.14]; high) and waist circumference (-1.16 cm [-1.93 to -0.39]; moderate). No differences were observed for other outcomes (very low-to-high). Current evidence provides a good indication that gamification features in apps targeting physical activity or measures of adiposity results in slight improvements in these outcomes compared to non-gamified versions. Recommendations to use an app for increasing physical activity or targeting weight loss should consider those with gamification features. None.

Background: Fructose-containing sugars as sugar-sweetened beverages (SSBs) may increase inflammatory biomarkers. Whether this effect is mediated by the food matrix at different levels of energy is unknown. To investigate the role of food source and energy, we conducted a systematic review and meta-analysis of controlled trials on the effect of different food sources of fructose-containing sugars on inflammatory markers at different levels of energy control. Methods: MEDLINE, Embase, and the Cochrane Library were searched through March 2022 for controlled feeding trials ≥ 7 days. Four trial designs were prespecified by energy control: substitution (energy matched replacement of sugars); addition (excess energy from sugars added to diets); subtraction (energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced). The primary outcome was C-reactive protein (CRP). Secondary outcomes were tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Independent reviewers extracted data and assessed risk of bias. GRADE assessed certainty of evidence. Results: We identified 64 controlled trials (91 trial comparisons, n = 4094) assessing 12 food sources (SSB; sweetened dairy; sweetened dairy alternative [soy]; 100% fruit juice; fruit; dried fruit; mixed fruit forms; sweetened cereal grains and bars; sweets and desserts; added nutritive [caloric] sweetener; mixed sources [with SSBs]; and mixed sources [without SSBs]) at 4 levels of energy control over a median 6-weeks in predominantly healthy mixed weight or overweight/obese adults. Total fructose-containing sugars decreased CRP in addition trials and had no effect in substitution, subtraction or ad libitum trials. No effect was observed on other outcomes at any level of energy control. There was evidence of interaction/influence by food source: substitution trials (sweetened dairy alternative (soy) and 100% fruit juice decreased, and mixed sources (with SSBs) increased CRP); and addition trials (fruit decreased CRP and TNF-α; sweets and desserts (dark chocolate) decreased IL-6). The certainty of evidence was moderate-to-low for the majority of analyses. Conclusions: Food source appears to mediate the effect of fructose-containing sugars on inflammatory markers over the short-to-medium term. The evidence provides good indication that mixed sources that contain SSBs increase CRP, while most other food sources have no effect with some sources (fruit, 100% fruit juice, sweetened soy beverage or dark chocolate) showing decreases, which may be dependent on energy control. Clinicaltrials.gov: (NCT02716870).

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.

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 .

Low- and no-calorie sweeteners (LNCS) (also referred to as non-nutritive sweeteners) have been the subject of controversy, especially considering recent conditional recommendations by the World Health Organization (WHO) not to use LNCS as a means of controlling weight and disease risk reduction. We summarize the data presented and discussions held between a panel of international nutrition research experts at a high-level Canadian Nutrition Society Thematic conference on “Non-nutritive sweeteners and health: unravelling the evidence and controversy”, which took place in Toronto, Canada on 27 January 2024. This paper summarizes the proceedings, including discussions on global sugar reduction policies, the toxicological safety and public perceptions of LNCS, divergence between public health and clinical practice guidance, and potential biological mechanisms underlying their effects. Randomized controlled trials show benefits of LNCS when substituting for sugars, while long-term cohort data have methodological limitations such as reverse causation and residual confounding. Mechanistic evidence does not support major adverse effects on energy intake regulation, glycemia, or gut microbiota. Together, these findings highlight the need for harmonized global policies, rigorous study designs that model real-world substitutions, and improved communication strategies to address misinformation.