Network Meta-analyses of Artificially Sweetened Beverages and Cardiometabolic Risk

Effect of Artificially Sweetened Beverages on Cardiometabolic Risk Factors: A Series of Systematic Reviews and Network Meta-analyses of Randomized Controlled Trials

Sugars especially in form or sugar-sweetened beverages (SSBs) have been singled out as one of the prime culprits in the dual epidemics of obesity and diabetes. Artificially sweetened beverages (ASBs) provide a potentially important means for displacing excess calories from free sugars in the diet. There is, however, a concern that the use of ASBs may themselves contribute to an increased risk of obesity and diabetes. This concern led the 2015 Dietary Guidelines for American Committee (DGAC) to recommend that sugars in the diet not be replaced with ASBs but rather with "healthy options" such as water. Whether ASBs as a replacement strategy for SSBs have the intended benefits and whether these benefits are similar to those of the preferred replacement strategy water remains unclear. To address this important question and update of the European Association of the Study (EASD) clinical practice guidelines for nutrition therapy, the investigators propose to conduct a series of systematic reviews and network meta-analyses of the totality of the evidence from randomized controlled trials to evaluate the effects of water and ASBs on incident overweight and obesity and cardiometabolic risk factors. The findings generated by this proposed knowledge synthesis will help improve the health of consumers through informing evidence/base guidelines and improving health outcomes by educating healthcare providers and patients, stimulating industry innovations, and guiding future research design.

Study Overview

• Status: Unknown
• Conditions: Obesity; Overweight
• Intervention / Treatment: Other: Diet beverages

Detailed Description

Background: Sugars especially in form or sugar-sweetened beverages (SSBs) have been singled out as one of the prime culprits in the dual epidemics of obesity and diabetes. Artificially sweetened beverages (ASBs) provide a potentially important means for displacing excess calories from free sugars in the diet. There is, however, a concern that the use of ASBs may themselves contribute to an increased risk of obesity and diabetes. This concern led the 2015 Dietary Guidelines for American Committee (DGAC) to recommend that sugars in the diet not be replaced with ASBs but rather with "healthy options" such as water. Whether ASBs as a replacement strategy for SSBs have the intended benefits and whether these benefits are similar to those of the preferred replacement strategy water remains unclear.

Objective: To inform the update of the European Association of the Study (EASD) clinical practice guidelines for nutrition therapy, the investigators will conduct a series of systematic reviews and network meta-analyses to asses the effect of the substitution of ASBs for SSBs, water for SSBs, and ASBs for water on measures of adiposity and cardiometabolic risk factors.

Design: Each systematic review and meta-analysis will be conducted according to the Cochrane Handbook for Systematic Reviews of Interventions and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Data sources: MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials (Clinical Trials; CENTRAL) will be searched using appropriate search terms supplemented by hand searches of references of included studies. Abstracts will be included and no language restrictions will be used.

Study selection: The investigators will include randomized controlled trials (RCTs) that are >=7 days duration and assess the effect of water versus ASBs on incident overweight/obesity or cardiometabolic risk factors.

Data extraction: Two or more investigators will independently extract relevant data and assess risk of bias using the Cochrane Risk of Bias Tool. All disagreements will be resolved by consensus. Standard computations and imputations will be used to derive missing variance data.

Outcomes: There will be 9 outcome clusters. The primary outcome will be body weight. Secondary outcomes will be other markers of adiposity (BMI, body fat, waist circumference); glycemic control (glycated blood proteins [HbA1c, fasting blood glucose, postprandial blood glucose, fasting blood insulin, homeostasis model assessment of insulin resistance [HOMA-IR]); established therapeutic lipid targets (LDL-cholesterol, non-HDL-cholesterol, apolipoprotein B [apo B], HDL-cholesterol, triglycerides, total cholesterol, ); blood pressure (systolic blood pressure and diastolic blood pressure); markers of NAFLD (intrahepatocellular lipids [IHCL], alanine aminotransferase [ALT], aspartate aminotransferase [AST]); and uric acid.

Data synthesis: Risk ratios (incident overweight/obesity) and mean differences (all other outcomes) will be pooled for direct comparisons (ASBs versus water) and indirect comparisons (ASBs versus SSBs and water versus SSBs using SSBs as the common comparator). We will perform Bayesian Network-Meta Analysis (NMA). We will present the pooled estimates as posterior means and 95% credible intervals. We will also use NMA for sensitivity analysis to validate our findings from the conventional generic inverse variance random-effects models. The NMA will be conducted using Markov Chain Monte Carlo (MCMC) approach simulation using GeMTC-R package. Paired analyses will be applied for crossover trials. Heterogeneity will be assessed by the Cochran Q statistic and quantified by the I2 statistic. To explore sources of heterogeneity, the investigators will conduct sensitivity analyses, in which each study is systematically removed. If there are >=10 studies, then the investigators will also explore sources of heterogeneity by a priori subgroup analyses by health status (metabolic syndrome/diabetes, overweight, normal weight), dose (<=median intake, >median intake), baseline measurements (global and abdominal adiposity), randomization, study design (parallel, crossover), energy balance (positive, neutral, negative), follow-up (<=8 weeks, >8 weeks), risk of bias, and individual domains of risk of bias using meta-regression analyses. Meta-regression analyses will assess the significance of categorical and continuous subgroup analyses. When >=10 studies are available, publication bias will be investigated by inspection of funnel plots and formal testing using the Egger test and the Begg test. If publication bias is suspected, then the investigators will attempt to adjust for funnel plot asymmetry by imputing the missing study data using the Duval and Tweedie trim and fill method.

Evidence Assessment: The certainty of the evidence for each outcome will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Knowledge translation plan: The results will be disseminated through interactive presentations at local, national, and international scientific meetings and publication in high impact factor journals. Target audiences will include the public health and scientific communities with interest in nutrition, diabetes, obesity and cardiovascular disease. Feedback will be incorporated and used to improve the public health message and key areas for future research will be defined. Applicant/Co-applicant decision makers will network among opinion leaders to increase awareness and participate directly as committee members in the development of future guidelines.

Significance: The proposed project will aid in knowledge translation related to the role of ASBs in the development of overweight and obesity, strengthening the evidence-base for guidelines and improving health outcomes by educating healthcare providers and patients, stimulating industry innovation, and guiding future research design.

• Study Type: Observational
• Enrollment (Anticipated): 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5C 2T2
      • The Toronto 3D (Diet, Digestive tract and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

All individuals, both children and adults, regardless of health status

Description

1. RCTs

   Inclusion Criteria:

   • Trials in humans
   • Diet beverage intervention
   • Water comparator
   • Diet duration >= 7 days
   • Viable outcome data

   Exclusion Criteria:

   • Non-human trials
   • Observational studies
   • Lack of suitable comparator
   • Diet duration < 2 weeks
   • No viable outcome data
2. Cohort studies

Inclusion Criteria:

• Prospective cohort studies or case-cohort studies
• Duration >= 1year
• Assessment of the exposure of diet beverages or water
• Ascertainment of viable data by level of exposure

Exclusion Criteria:

• Ecological, cross-sectional, and retrospective observational studies, clinical trials and non-human studies
• Duration < 1 year
• No assessment of exposures of diet beverages or water
• No ascertainment viable clinical outcome data by level of exposure

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adiposity - Body weight	body weight	Up to 20 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adiposity - BMI	Body mass index (BMI) in kg/m2	Up to 20 years
Adiposity - Body fat	Body fat in % (relative units)	Up to 20 years
Adiposity - waist circumference (WC)	Waist circumference in cm	Up to 20 years
Glycemic control - HbA1c	HbA1c in % (absolute units)	Up to 20 years
Glycemic control - fasting plasma glucose (FPG)	Fasting plasma glucose (FPG) in mmol/L	Up to 20 years
Glycemic control - 2h plasma glucose (2h-PG)	2h plasma glucose (2h-PG) during a 75g oral glucose tolerance test (OGTT) in mmol/L	Up to 20 years
Glycemic control - fasting plasma insulin (FPI)	Fasting plasma insulin (FPI) in pmol/L	Up to 20 years
Glycemic control - homeostasis model assessment of insulin resistance (HOMA-IR)	Homeostasis model assessment of insulin resistance (HOMA-IR)	Up to 20 years
Blood lipid targets - LDL-cholesterol (LDL-C)	LDL-cholesterol (LDL-C) in mmol/L	Up to 20 years
Blood lipid targets - non-HDL-cholesterol (non-HDL-C)	non-HDL-cholesterol (non-HDL-C) in mmol/L	Up to 20 years
Blood lipid targets - apolipoprotein B (apo B)	Apolipoprotein B (apo B) in g/L	Up to 20 years
Blood lipid targets - triglycerides	Triglycerides in mmol/L	Up to 20 years
Blood lipid targets - HDL-cholesterol (HDL-C)	HDL-cholesterol (HDL-C) in mmol/L	Up to 20 years
Blood lipid targets - Total-cholesterol (Total-C)	Total-cholesterol (Total-C) in mmol/L	Up to 20 years
Blood pressure - Systolic blood pressure (SBP)	Systolic blood pressure (SBP) in mmHg	Up to 20 years
Blood pressure - diastolic blood pressure (DBP)	Diastolic blood pressure (DBP) in mmHg	Up to 20 years
Markers of non-alcoholic fatty liver disease (NAFLD) - Intrahepatocellular lipids (IHCL)	Intrahepatocellular lipids (IHCL) in % (relative units)	Up to 20 years
Markers of non-alcoholic fatty liver disease (NAFLD) - alanine transaminase (ALT)	Alanine transaminase (ALT) in U/L	Up to 20 years
Markers of non-alcoholic fatty liver disease (NAFLD) - aspartate transaminase (AST)	Aspartate transaminase (AST) in U/L	Up to 20 years
Uric acid	Uric acid in mmol/L	Up to 20 years

Collaborators and Investigators

• Sponsor: John Sievenpiper

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (Anticipated): March 1, 2020
• Study Completion (Anticipated): March 1, 2020

Study Registration Dates

• First Submitted: August 22, 2016
• First Submitted That Met QC Criteria: August 24, 2016
• First Posted (Estimate): August 25, 2016

Study Record Updates

• Last Update Posted (Actual): February 25, 2020
• Last Update Submitted That Met QC Criteria: February 21, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Obesity; Overweight; Evidence-based nutrition (EBN); Randomized controlled trials; Body weight; Systematic review and meta-analysis; Evidence-based medicine (EBM); Clinical practice guidelines; Body mass index; Adiposity; Prospective cohort studies
• Additional Relevant MeSH Terms: Body Weight; Overweight
• Other Study ID Numbers: DNSG-LCSBs

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO