Meta-analyses of Total and Individual Fructose-containing Sugars and Incident Cardiometabolic Disease
Meta-analyses of Total and Individual Fructose-containing Sugars and Incident Cardiometabolic Disease
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 and increasing burden of cardiometabolic disease. Despite the uncertainties
 in the evidence, 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 role of fructose-containing sugars in the development of
 overweight/obesity, diabetes, hypertension, gout, and cardiovascular disease, by undertaking
 a series of systematic syntheses of the available prospective cohort studies. Prospective
 cohort studies have the advantage of relating "real world" intakes of sugars to clinically
 meaningful disease endpoints over long durations of follow-up. 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 and increasing burden of cardiometabolic disease. 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 ecological analyses which have linked increasing fructose
 intake with increasing obesity, diabetes, and hypertension rates and animal models of
 fructose induced metabolic syndrome and hypertension, which overfeed fructose at levels of
 exposure far beyond actual population levels of intake, have been used to underpin this
 debate. Evidence from well-adjusted prospective cohort studies also suggest a positive
 association between the consumption of sugar-sweetened beverages and increased energy
 consumption and weight gain. But not all meta-analyses of the available prospective cohort
 studies have supported this conclusion for SSBs, and no meta-analyses have investigated the
 effect of total fructose-containing sugars which also include grain and fruit sources on
 incident overweight/obesity, diabetes, metabolic syndrome, hypertension, gout, and
 cardiovascular disease. Despite the limitations in extrapolating from the available
 observational data and their inconsistency with data from controlled trials in humans (the
 highest level of evidence used in evidence based medicine) which do not show any adverse
 metabolic effects under isocaloric feeding conditions, the heart and diabetes associations
 have taken a risk reduction approach to added fructose-containing sugars, setting highly
 restrictive upper thresholds for their intake to achieve and maintain healthy body-weights
 and avoid adverse lipid effects.

 Objective: To improve the evidence on which recommendations and public health policy are
 based, we will conduct a series of systematic reviews and meta-analyses of the role of
 fructose-containing sugars in the development of cardiometabolic disease in prospective
 cohort studies. A total of 5 analyses are proposed: (1)overweight/obesity, (2)
 diabetes/metabolic syndrome, (3) hypertension, (4) gout, and (5) coronary heart disease
 (CHD).

 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 Meta-analysis
 Of Observational Studies in Epidemiology (MOOSE) 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 prospective cohort studies investigating the relation of
 fructose-containing (fructose, sucrose, and HFCS) sugars to incident overweight/obesity,
 diabetes, metabolic syndrome, hypertension, gout, and cardiovascular disease.

 Data extraction. Two investigators will independently extract information about study design,
 sample size, subject characteristics, fructose form, fructose exposure levels,
 duration/person-years of follow-up, background diet profile, adjustments of models. Risk
 ratios for clinical outcomes will be extracted or derived from clinical event data across
 quantiles of exposure. Risk of bias will be assessed using the Cochrane Risk of Bias tool.

 Outcomes: Each of the 5 proposed analyses will assess a different cardiometabolic disease
 outcome: (1) overweight/obesity, (2) diabetes/metabolic syndrome, (3) hypertension, (4) gout,
 and (5) CHD.

 Data synthesis. The natural log-transformed relative risks of clinical outcomes comparing the
 highest exposure level to the reference group from each cohort will be pooled using the
 generic inverse variance method with random effects models. Heterogeneity will be assessed by
 Cochrane's Q 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, sex, sugar type (fructose, sucrose, HFCS), follow-up (<10-years, >=10-years), level
 of adjustment of models, and Cochrane risk of bias on the effect of fructose. Significant
 unexplained heterogeneity will be investigated by additional post hoc subgroup analyses.
 Meta-regression analyses will assess the significance of subgroups analyses. Dose-response
 analyses will be undertaken using random-effects generalized least squares trend estimation
 models (GLST), appropriate for weighted regression of summarized dose-response data with
 dependent components(i.e. the reference exposure level). If insufficient evidence of a linear
 relationship is found, then we will do spline curve modeling (the MKSPLINE procedure) to
 characterize segments of the dose response curve where a linear approximation best describes
 the data. Publication bias will be assessed by the inspection of funnel plots and using
 Begg's and Egger's tests.

 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: To address the uncertainties in the evidence, we conducted a series of
 Canadian Institutes of Health Research (CIHR) funded systematic reviews and meta-analyses of
 controlled feeding trials of the effect of fructose on cardiometabolic risk
 (ClinicalTrials.gov registration number: NCT01363791). We found that fructose in isocaloric
 substitution for other sources of carbohydrate (isocaloric trials) does not increase body
 weight, lipids, blood pressure, uric acid, or insulin and even improves glycemic control.
 There was, however, a signal for harm under certain conditions. High doses of fructose
 increased triglycerides in isocaloric trials, and fructose providing excess energy at extreme
 doses relative to control diets (hypercaloric trials) also increased body weight,
 triglycerides, and uric acid. The implications of these findings for "real world" dietary
 advice, however, were complicated by several factors. First, fructose is not commonly
 consumed in isolation as a sweetener. Sucrose and HFCS are the primary fructose-containing
 sweeteners in the U.S. diet. Second, the level of fructose exposure in the available trials
 was well above population levels of intake, exceeding the 95th-percentile for U.S. intake in
 most of the isocaloric trials and in all of the hypercaloric trials, in which the excess
 energy brought by fructose was an important source of confounding. Finally, the available
 trials investigated effects on biomarkers of disease and not clinically meaningful events.
 The proposed systematic review and meta-analyses of prospective cohort studies will address
 these limitations directly by investigating the relation of self-reported, "real world"
 intakes of all fructose-containing sugars (fructose, sucrose, and HFCS) to the development
 overweight/obesity, diabetes/metabolic syndrome, hypertension, gout, and cardiovascular
 disease.

 Significance: The proposed project will aid in knowledge translation related to the effects
 of dietary fructose on overweight/obesity, diabetes/metabolic syndrome, hypertension, gout,
 and cardiovascular disease, strengthening the evidence-base for recommendations and improving
 health outcomes through informing consumers and guiding future research.
Inclusion Criteria:

 -  Prospective observational studies

 -  Assessment of fructose-containing sugar exposure

 -  Viable clinical outcome data by level of exposure

 Exclusion Criteria:

 -  Ecological, cross-sectional, and retrospective observational studies, clinical trials,
 and non-human studies

 -  No assessment of fructose-containing sugar exposure

 -  No viable clinical outcome data by level of exposure