Since uncontrolled observational studies first linked fructose to the epidemic of obesity almost a decade ago, it has become a focus of intense concern regarding its role in the obesity epidemic. Despite the uncertainties in the evidence,the recommendations of international health organizations have cautioned against moderate to high intakes fructose-containing sugars, especially those from sugar sweetened beverages (SSBs). To improve the evidence on which nutrition recommendations are based, the investigators propose to study of the effect of fructose-containing sugar sweetened beverages (SSBs)on body weight, by undertaking a systematic synthesis of the data taken from all available clinical studies in humans. This technique has the strength of allowing all of the available data to be pooled together and differences to be explored in groups of different study participants (healthy humans of different sex, weight, and age and in those with diseases which predispose to disturbances in metabolism, such as diabetes) with dietary fructose in different forms, doses, and with differing durations of exposure. The findings generated by this proposed knowledge synthesis will help improve the health of consumers through informing recommendations for the general public, as well as those at risk of diabetes and cardiovascular disease.

Background: Fructose has become a focus of intense concern regarding its links to the obesity epidemic. There have been dozens of editorials, commentaries, and letters in the scientific literature and numerous pieces in the lay and social media calling for efforts to restrict its intake and even regulate it like tobacco or alcohol. Uncontrolled observational studies which have linked increasing fructose intake with increasing obesity rates since the 1970s and animal models of fructose overfeeding at levels of exposure far beyond actual population levels of intake have been used to underpin this debate. Evidence from observational studies and controlled feeding trials also suggest a positive association between the consumption of fructose-containing sugar-sweetened beverages, in which high fructose corn syrup (HFCS) is the main sweetener, and increased energy consumption and weight gain, but not all meta-analyses have supported this conclusion. Despite the limitations in extrapolating from these data and their inconsistency with data from controlled trials in humans (the highest level of evidence used in evidence based medicine), the American Heart Association (AHA) have taken a risk reduction approach to added fructose-containing sugars, especially those from sugar sweetened beverages (SSBs), setting highly restrictive upper thresholds for their intake to achieve and maintain healthy body-weights.

Objective: To improve the evidence on which recommendations and public health policy are based, we propose to conduct a systematic review and meta-analysis of the effect of fructose-containing SSBs on body weight in controlled feeding trials.

Design: The planning and conduct of the proposed meta-analyses will follow the Cochrane handbook for systematic reviews of interventions. The reporting will follow the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.

Data sources. MEDLINE, EMBASE, CINAHL and The Cochrane Central Register of Controlled Trials (Clinical Trials; CENTRAL) will be searched using appropriate search terms, supplemented by manual, hand searches of bibliographies.

Study selection: We will include controlled feeding trials investigating the effect of fructose-containing (fructose, sucrose, and HFCS) SSBs in isocaloric exchange for other carbohydrate sources (isocaloric trials) or hypercaloric exchange for beverages containing a non-nutritive sweetener or added to a control diet as a source of excess energy (hypercaloric trials) on body weight in humans. Studies that are <7-days diet duration, lack a control, or do not provide viable endpoint data will be excluded.

Data extraction. Two investigators will independently extract information about study design, sample size, subject characteristics, fructose form, dose, reference-carbohydrate, follow-up, and background diet profile. Mean±SEM values will be extracted for body weight. Standard computations and imputations will be used to derive missing variance data. The quality/validity of each study will be assessed using the Heyland Methodological Quality Score (MQS).

Ouctomes: Body weight change will be the only ouctome.

Data synthesis. Meta-analyses will be conducted using the Generic Inverse Variance method applying random effects models expressed as standardized mean differences (SMDs) with 95% CIs. Paired analyses will be applied for crossover trials. Heterogeneity will be assessed by the Q statistic and quantified by I2. Sensitivity analyses and a priori subgroup analyses will be undertaken to explore sources of heterogeneity including the effect of underlying disease status, sugar type (fructose, sucrose, HFCS), reference carbohydrate (comparator), fructose form, dose, follow-up, study design, baseline measurements, and study quality on the effect of fructose. Significant unexplained heterogeneity will be investigated by additional post hoc subgroup analyses (e.g. age, sex, level of feeding control, energy balance and composition of the background diet, etc.). Meta-regression analyses will assess the significance of subgroups analyses. Publication bias will be investigated by inspection of funnel plots.

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.

Preliminary findings: We conducted a systematic review and meta-analysis to investigate the effect of dietary fructose on body weight in controlled feeding trials (Sievenpiper et al. Ann Intern Med. 2012;156:291-304). We identified 31 isocaloric trials (n=635), in which fructose was exchanged for the same amount of carbohydrate in the diet, and 10 hypercaloric trials (n=119), in which the diet was supplemented with excess energy from high-dose fructose. Whereas there was no effect of fructose under isocaloric trial conditions, fructose under hypercaloric trial conditions (+104-250-g/day, +18-97% energy) significantly and consistently increased weight (MD=0.53-kg or 1.17-lb [95%CI: 0.26 to 0.79-kg or 0.57 to 1.74-lb]). In both analyses, fructose behaved no differently than sucrose or HFCS, where these sugars were the comparators, and fructose in fluid (beverage) form did not increase body weight in the isocaloric trials. We concluded that the available trials did not support a body weight raising-effect of fructose in isocaloric exchange for other carbohydrate. There was, however, consistent evidence for a modest body weight raising-effect of fructose at extreme doses providing excess energy, where the effect of energy appeared to be dominant. The implications of our findings for "real world" dietary advice was complicated by the fact that sucrose and HFCS are the primary fructose-containing sweeteners in the US diet. The proposed systematic review and meta-analysis will address this limitation directly by investigating the effect of all fructose-containing (fructose, sucrose, and HFCS) SSBs.

Significance: The proposed project will aid in knowledge translation related to the effects of dietary fructose on overweight and obesity, strengthening the evidence-base for recommendations and improving health outcomes through informing consumers and guiding future research.

Inclusion Criteria:

• Trials in humans
• Oral fructose intervention
• Suitable control (i.e. another carbohydrate source in isocaloric exchange for fructose or a control diet which is compared with the same diet supplemented with excess energy from fructose)
• >= 7-days diet duration
• Viable endpoint data

Exclusion Criteria:

• Non-human studies
• IV or parenteral fructose
• High fructose corn syrup or sucrose intervention (except where these are the comparators)
• Lack of a suitable control
• < 7-days diet duration.
• No viable endpoint data

Varied