Meta-analysis of Low-calorie Sweetened Beverages and Cardiometabolic Outcomes

Study Overview
=================
Brief Summary
-----------------
We propose to conduct a systematic literature review and meta-analysis to assess the association of low-calorie sweetened beverages (LCSBs) on cardiometabolic outcomes in prospective cohort studies. We will be using methodological approaches (change in LCSBs intake, and/or substitution analysis) that attempt to overcome the issue of reverse causality associated with studies of LCSBs and cardiometabolic disease. Ten cardiometabolic outcomes will be assessed: Global adiposity - body weight Global adiposity - BMI Global adiposity - body fat Abdominal adiposity - waist circumference Overweight/obesity incidence Metabolic syndrome incidence Type 2 diabetes incidence Cardiovascular disease incidence Cardiovascular disease mortality Total mortality

Detailed Description
-----------------
Background: Low-calorie sweetened beverages (LCSBs) may provide a potentially important means for displacing excess calories from free sugars in the diet. However, prospective cohort studies suggest that the use of LCSBs may contribute to an increased risk of obesity and diabetes. These findings are likely due to methodological limitations of study design and analysis that do not account for reverse causality, where higher risk of cardiometabolic outcomes may lead to people to switch to LCSBs. There is a need for a systematic review and meta-analysis (SRMA) of prospective cohort studies to overcome these methodological limitations. Objective: We will conduct a SRMA of prospective cohort studies in human subjects that have assessed cardiometabolic outcomes using two analytical strategies: i) Assessment of change in intake of LCSBs with change in outcome (change analysis) ii) Assessment of substitution of LCSBs for sugar-sweetened beverages (SSBs) or water. Design: We will conduct a SRMA according to the Cochrane Handbook for Systematic Reviews of Interventions and report the findings according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Data sources: MEDLINE, EMBASE, and the Cochrane Library databases will be searched using appropriate search terms, supplemented by hand searches of references of included studies. No restriction will be placed on language. Study selection: Prospective cohort studies reporting (a) change analysis (change in intake of LCSBs with the change in outcome), and/or (b) substitution analysis (substitution of SSBs with LCSBs or water) with more than 1-year of follow-up will be used. Cohort studies that have a follow-up duration <1 year, do not report assessment of exposure, or do not provide viable outcome data by level of exposure will be excluded. Data extraction Two or more investigators will independently extract relevant data and assess risk of bias using the Newcastle-Ottawa Scale (NOS) for prospective cohorts. All disagreements will be resolved by consensus. Risk ratios (RRs), odds ratios (ORs) and hazard ratios (HRs) for clinical outcomes in the prospective cohort studies will be extracted or derived from clinical event data across exposure categories. Outcomes: Ten cardiometabolic health outcomes will be assessed: Global adiposity - body weight Global adiposity - BMI Global adiposity - body fat Abdominal adiposity - waist circumference Overweight/obesity incidence Metabolic syndrome incidence Type 2 diabetes incidence Cardiovascular disease incidence Cardiovascular disease mortality Total mortality Data synthesis: Natural log-transformed RRs or HRs of clinical outcomes, comparing extreme quantiles (the highest exposure versus the lowest exposure or reference group), will be pooled separately using the generic inverse variance method with random effects models and expressed as RRs with 95% confidence intervals (CIs). Heterogeneity will be tested by Cochran's Q statistic and quantified by the I2 statistic. To explore sources of heterogeneity, we will conduct sensitivity analyses, in which each study is systematically removed. If ≥10 cohort comparisons are available, then we will perform an a-priori subgroup analyses by meta-regression for follow-up (<10 years vs. ≥10 years), sex (males vs. females, males vs. mixed, females vs. mixed), study quality (NOS <6 vs. ≥6) and funding source. Significant unexplained heterogeneity will be investigated by additional post hoc subgroup analyses and influence analysis. A study will be considered influential if it changes the direction or significance of the pooled estimates or the evidence of heterogeneity. Dose response estimates will be pooled using one-stage linear mixed model. When ≥10 studies are available, publication bias will be investigated by inspection of funnel plots and formal testing using the Egger and Begg tests. If publication bias is suspected, we 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 overall certainty of evidence for each outcome will be assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). 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 to the role of the LCSBs role as a replacement strategy for SSBs, strengthening the evidence-base for guidelines and improving health outcomes by educating healthcare providers and patients, stimulating industry innovation, and guiding future research design.

Official Title
-----------------
Changing or Substituting Low-calorie Sweetened Beverages for Sugar-Sweetened Beverages or Water and Cardiometabolic Outcomes: A Systematic Review and Meta-analysis of Prospective Cohort Studies

Conditions
-----------------
Adiposity, Metabolic Syndrome, Type 2 Diabetes, Cardiovascular Diseases, Mortality

Intervention / Treatment
-----------------
* Other: Change in LCSBs Intake
* Other: Substitute LCSBs for SSBs or Water


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Prospective cohorts studies Duration: more than 1 year follow-up Exposure: LCSBs Change analysis or substitution analysis of exposure Exclusion Criteria: Non-human studies Less than 1 year follow-up Analysis of baseline or prevalent intake of exposure only
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Low-calorie Sweetened Beverages (LCSBs)<br>Beverages exclusively using zero-energy (e.g., acesulfame-potassium, aspartame, cyclamate, saccharin, sucralose, advantame, neotame), and /or reduced-energy food additives (e.g., stevia, monk fruit). | Other: Change in LCSBs Intake<br>* Effect of changing LCSBs intake<br>Other: Substitute LCSBs for SSBs or Water<br>* Effect of substituting LCSBs for SSBs or Water<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global measures of adiposity with established clinical relevance - body weight | Change in body weight | More than 1 year | 
| Global measures of adiposity with established clinical relevance - BMI | Change in body mass index (BMI) | More than 1 year | 
| Global measures of adiposity with established clinical relevance - body fat | Change in body fat | More than 1 year | 
| Abdominal measures of adiposity with established clinical relevance - waist circumference | Change in waist circumference | More than 1 year | 
| Overweight/obesity incidence | Risk ratio of Overweight/obesity incidence | More than 1 year | 
| Metabolic syndrome incidence | Risk ratio of metabolic syndrome incidence | More than 1 year | 
| Type 2 diabetes incidence | Risk ratio of type 2 diabetes incidence | More than 1 year | 
| Cardiovascular disease incidence | Risk ratio of cardiovascular disease incidence | More than 1 year | 
| Cardiovascular disease mortality | Risk ratio of Cardiovascular disease mortality | More than 1 year | 
| Total mortality | Risk ratio of total mortality | More than 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
body weight, BMI, waist circumference, diabetes, cardiovascular disease, metabolic syndrome, mortality, overweight incidence, obesity incdience