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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/m 2 ) 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: 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: 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.

Background: The Dietary Approaches to Stop Hypertension (DASH) dietary pattern, which emphasizes fruit, vegetables, fat-free/low-fat dairy, whole grains, nuts and legumes, and limits saturated fat, cholesterol, red and processed meats, sweets, added sugars, salt and sugar-sweetened beverages, is widely recommended by international diabetes and heart association guidelines., Objective: To summarize the available evidence for the update of the European Association of the Study of Diabetes (EASD) guidelines, we conducted an umbrella review of existing systematic reviews and meta-analyses using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach of the relation of the DASH dietary pattern with cardiovascular disease and other cardiometabolic outcomes in prospective cohort studies and its effect on blood pressure and other cardiometabolic risk factors in controlled trials in individuals with and without diabetes., Methods: MEDLINE and EMBASE were searched through 3 January 2019. We included systematic reviews and meta-analyses assessing the relation of the DASH dietary pattern with cardiometabolic disease outcomes in prospective cohort studies and the effect on cardiometabolic risk factors in randomized and non-randomized controlled trials. Two independent reviewers extracted relevant data and assessed the risk of bias of individual studies. The primary outcome was incident cardiovascular disease (CVD) in the prospective cohort studies and systolic blood pressure in the controlled trials. Secondary outcomes included incident coronary heart disease, stroke, and diabetes in prospective cohort studies and other established cardiometabolic risk factors in controlled trials. If the search did not identify an existing systematic review and meta-analysis on a pre-specified outcome, then we conducted our own systematic review and meta-analysis. The evidence was summarized as risk ratios (RR) for disease incidence outcomes and mean differences (MDs) for risk factor outcomes with 95% confidence intervals (95% CIs). The certainty of the evidence was assessed using GRADE., Results: We identified three systematic reviews and meta-analyses of 15 unique prospective cohort studies ( n = 942,140) and four systematic reviews and meta-analyses of 31 unique controlled trials ( n = 4,414) across outcomes. We conducted our own systematic review and meta-analysis of 2 controlled trials ( n = 65) for HbA1c. The DASH dietary pattern was associated with decreased incident cardiovascular disease (RR, 0.80 (0.76⁻0.85)), coronary heart disease (0.79 (0.71⁻0.88)), stroke (0.81 (0.72⁻0.92)), and diabetes (0.82 (0.74⁻0.92)) in prospective cohort studies and decreased systolic (MD, -5.2 mmHg (95% CI, -7.0 to -3.4)) and diastolic (-2.60 mmHg (-3.50 to -1.70)) blood pressure, Total-C (-0.20 mmol/L (-0.31 to -0.10)), LDL-C (-0.10 mmol/L (-0.20 to -0.01)), HbA1c (-0.53% (-0.62, -0.43)), fasting blood insulin (-0.15 μU/mL (-0.22 to -0.08)), and body weight (-1.42 kg (-2.03 to -0.82)) in controlled trials. There was no effect on HDL-C, triglycerides, fasting blood glucose, HOMA-IR, or CRP. The certainty of the evidence was moderate for SBP and low for CVD incidence and ranged from very low to moderate for the secondary outcomes., Conclusions: Current evidence allows for the conclusion that the DASH dietary pattern is associated with decreased incidence of cardiovascular disease and improves blood pressure with evidence of other cardiometabolic advantages in people with and without diabetes. More research is needed to improve the certainty of the estimates.

Objective: Contrary to the concerns that fructose may have adverse metabolic effects, an emerging literature has shown that small doses (≤10 g/meal) of fructose and its low-caloric epimers (allulose, tagatose, and sorbose) decrease the glycemic response to high glycemic index meals. Whether these acute reductions manifest as sustainable improvements in glycemic control is unclear. Our objective was to synthesize the evidence from controlled feeding trials that assessed the effect of small doses of fructose and its low-caloric epimers on glycemic control. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library through April 18, 2018. We included controlled feeding trials of ≥1 week that investigated the effect of small doses (≤50 g/day or ≤10% of total energy intake/day) of fructose and its low-caloric epimers on HbA 1c , fasting glucose, and fasting insulin. Two independent reviewers extracted data and assessed risk of bias. Data were pooled using the generic inverse variance method and expressed as mean differences (MDs) with 95% confidence intervals (CIs). Heterogeneity was assessed using the Cochran Q statistic and quantified using the I ² statistic. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessed the certainty of the evidence. Results: We identified 14 trial comparisons ( N = 337) of the effect of fructose in individuals with and without diabetes, 3 trial comparisons ( N = 138) of the effect of allulose in individuals without diabetes, 3 trial comparisons ( N = 376) of the effect of tagatose mainly in individuals with type 2 diabetes, and 0 trial comparisons of the effect of sorbose. Small doses of fructose and tagatose significantly reduced HbA 1c (MD = -0.38% (95% CI: -0.64%, -0.13%); MD = -0.20% (95% CI: -0.34%, -0.06%)) and fasting glucose (MD = -0.13 mmol/L (95% CI: -0.24 mmol/L, -0.03 mmol/L)); MD = -0.30 mmol/L (95% CI: -0.57 mmol/L, -0.04 mmol/L)) without affecting fasting insulin ( p > 0.05). Small doses of allulose did not have a significant effect on HbA 1c and fasting insulin ( p > 0.05), while the reduction in fasting glucose was of borderline significance ( p = 0.05). The certainty of the evidence of the effect of small doses of fructose and allulose on HbA 1c , fasting glucose, and fasting insulin was graded as low. The certainty of the evidence of the effect of tagatose on HbA 1c , fasting glucose, and fasting insulin was graded as moderate. Conclusions: Our results indicate that small doses of fructose and tagatose may improve glycemic control over the long term. There is a need for long-term randomized controlled trials for all four sugars to improve our certainty in the estimates.

Recent literature suggests that catalytic doses (&le;10 g/meal or 36 g/day) of D-fructose and D-allulose may reduce postprandial blood glucose responses to carbohydrate loads in people with and without type 2 diabetes by inducing glycogen synthesis. To assess the effect of small single doses of fructose and allulose on postprandial blood glucose regulation in response to a 75 g-oral glucose tolerance test (75 g-OGTT) in healthy individuals, we conducted an acute randomized, crossover, equivalence trial in healthy adults. Each participant randomly received six treatments, separated by a minimum one-week washout. Treatments consisted of a 75 g-OGTT with the addition of fructose or allulose at 0 g (control), 5 g or 10 g. A standard 75 g-OGTT protocol was followed with blood samples at &minus;30, 0, 30, 60, 90, 120 min. The primary outcome was the difference in plasma glucose incremental area under the curve (iAUC). A total of 27 participants underwent randomization with data available from 25 participants. Small doses of fructose or allulose did not show a significant effect on plasma glucose iAUC or other secondary markers of postprandial blood glucose regulation in response to a 75 g-OGTT in healthy individuals. These results were limited by the low power to detect a significant difference, owing to greater than expected intra-individual coefficient of variation (CV) in plasma glucose iAUC. Overall, we failed to confirm the catalytic effects of small doses of fructose and allulose in healthy individuals. Future trials may consider recruiting larger sample sizes of healthy individuals., Trial Registration: clinicaltrials.gov identifier, NCT02459834.

Unlabelled: Previous research on the effect of replacing sources of animal protein with plant protein on glycemic control has been inconsistent. We therefore conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effect of this replacement on glycemic control in individuals with diabetes. We searched MEDLINE, EMBASE, and Cochrane databases through 26 August 2015. We included RCTs ≥ 3-weeks comparing the effect of replacing animal with plant protein on HbA1c, fasting glucose (FG), and fasting insulin (FI). Two independent reviewers extracted relevant data, assessed study quality and risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences (MD) with 95% confidence intervals (CIs). Heterogeneity was assessed (Cochran Q-statistic) and quantified (I²-statistic). Thirteen RCTs (n = 280) met the eligibility criteria. Diets emphasizing a replacement of animal with plant protein at a median level of ~35% of total protein per day significantly lowered HbA1c (MD = -0.15%; 95%-CI: -0.26, -0.05%), FG (MD = -0.53 mmol/L; 95%-CI: -0.92, -0.13 mmol/L) and FI (MD = -10.09 pmol/L; 95%-CI: -17.31, -2.86 pmol/L) compared with control arms. Overall, the results indicate that replacing sources of animal with plant protein leads to modest improvements in glycemic control in individuals with diabetes. Owing to uncertainties in our analyses there is a need for larger, longer, higher quality trials., Trial Registration: ClinicalTrials.gov registration number: NCT02037321.