Obesity Clinical Trial
Official title:
The Relation of Fructose-containing Sugars to Incident Cardiometabolic Disease: Systematic Reviews and Meta-analyses of Prospective Observational Studies to Provide Evidence-based Guidance for Nutrition Guidelines Development
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.
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