There is an urgent need for stronger evidence to support recommendations for the role of sugars in diabetes and related cardiometabolic diseases. Although large prospective cohort studies have shown a significant positive association of fructose-containing sugars-sweetened beverages with incident obesity, diabetes, heart disease, and stroke, these associations do not appear to hold true for total fructose-containing sugars and other important sources of free fructose-containing sugars such as pure fruit juice, yogurt, or even cakes and sweets. As dietary guidelines have moved away from macronutrient centric recommendations towards more food and dietary-pattern based recommendations, this inconsistency in the data has not been appreciated. There remains a focus on free sugars, in the absence of sufficient information on the role of different food sources of fructose-containing sugars in diabetes and related cardiometabolic diseases. A systematic review and meta-analysis of prospective cohort studies is considered to be the "Gold Standard" of evidence. To provide evidence-based guidance to support the development of public health policy in relation sugars and the primary prevention of diabetes, we will conduct a series of systematic reviews and meta-analyses of the relation of food sources of fructose-containing sugars with incident type 2 diabetes and related cardiometabolic diseases in prospective cohort studies.

Background: Sugars have emerged as one of the most important public health targets. Attention has focused on the special role of fructose based on its unique biochemical, metabolic, and endocrine responses. These mechanisms, however, have failed to translate into clinically meaningful effects in calorie-matched comparisons with other sources of carbohydrate. Sugars-sweetened beverage (SSBs) appear to be the special case. Whereas large prospective cohort studies have shown a consistent relation of SSBs with incident obesity, diabetes, metabolic syndrome (MetS), hypertension, coronary heart disease (CHD), stroke, and gout, associations have not been shown when modeling total sugars (with the exception of gout) or other food sources of added/free sugars such as pure fruit juices, yogurt, or even sweets. In the absence of a clear signal for sugars alone, it is unclear whether the associations seen for SSBs hold for other important food sources of sugars.

Need for a review: As dietary guidelines and public health policy have shifted toward food and dietary-pattern based recommendations, the lack of high quality syntheses and translation of the role of different food sources of sugars in cardiometabolic diseases represents an urgent call for stronger evidence to support guidelines development.

Objectives: To build on our previous work, we will conduct a series of systematic reviews and meta-analyses to compare important food sources of added/free sugars (SSBs, pure fruit juice, yogurt, sweets, cereals, etc). in their relation with incident cardiometabolic diseases.

Design: Our proposed series of systematic reviews and meta-analyses will follow the same successful protocol we used for our previous CIHR-funded knowledge synthesis of fructose and cardiometabolic risk (clinicaltrials.gov, NCT01363791). The knowledge syntheses 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 library will be searched.

Study selection: We will include cohorts assessing the relation of different food sources of fructose-containing sugars (SSBs, pure fruit juice, yogurt, sweets, cereals, etc) with incident type 2 diabetes, MetS, hypertension, CHD, stroke, and gout.

Data extraction: Two investigators will independently extract relevant data and assess risk of bias.

Outcomes: We will assess 6 outcomes: type 2 diabetes, MetS, hypertension, CHD, stroke, and gout.

Data synthesis: Risk ratios will be pooled using the generic inverse variance method for each food source of fructose-containing sugars. Random-effects models will be used even in the absence of statistically significant between-study heterogeneity, as they yield more conservative summary effect estimates in the presence of residual heterogeneity. Fixed-effects models will only be used where there is <5 included studies. 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 (follow-up, adjustments, exposure assessment, dose, outcome ascertainment, risk of bias). Meta-regression analyses will assess the significance of categorical and continuous subgroups analyses. 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, 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 strength of the evidence for each outcome will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE).

Knowledge translation plan: We will follow the Ottawa model. Results will be disseminated through presentations at scientific meetings and publication in high impact journals. Webcasts and social media posts on YouTube videos, Facebook, twitter and LinkedIn will also be used. Target adopters will include clinicians, allied health professionals, policy makers, industry, researchers, and patient groups.

Significance: The proposed project will aid in knowledge translation related to the health effects of food sources of sugars, informing evidence-based guidelines and improving health outcomes by educating healthcare providers and patients, stimulating industry innovation, and guiding future research design.

Prospective cohort studies

Inclusion Criteria

• Prospective cohort studies or case-cohort studies
• Duration >= 1 year
• Assessment of the exposure of fructose-containing sugars or important food sources
• 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 fructose-containing sugars or important food sources
• No ascertainment viable clinical outcome data by level of exposure

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