Meta-analyses of Fructose and Cardiometabolic Risk

May 26, 2015 updated by: John Sievenpiper

Effect of Fructose on Metabolic Control in Humans: A Series of Systematic Reviews and Meta-analyses to Provide Evidence-based Guidance for Nutrition Guidelines Development

Diabetes and heart associations continue to discourage high intakes of dietary fructose, a constituent part of the sucrose molecule that is found in fruits and vegetables as a natural sugar and in some processed foods and beverages as an added sweetener. The concern relates to its ability to increase certain blood fats and cholesterol, which increase the risk of cardiovascular disease. The evidence for an adverse effect of fructose on these risk factors, however, is inconclusive. To improve the evidence on which nutrition recommendations for fructose are based, the investigators therefore propose to study the effect of fructose on blood fats, cholesterol, sugars, blood pressure, and 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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Background: Fructose has been implicated in chronic disease guidelines. The American Heart Association (AHA) and American (ADA), Canadian (CDA), and European (EASD) Diabetes Associations discourage dietary fructose at high intakes (>15-20% energy), citing its ability to aggravate blood lipids. The American Heart Association (AHA) and the World Health Organization (WHO) recommend reduced consumption (<5-7% and <10% energy, respectively) of added sugars, especially as high fructose corn syrup in sugar sweetened beverages, to decrease the risk of weight gain. These concerns, however, are based on inconsistent intervention data in humans. There is also paradoxical evidence that small, catalytic doses of fructose at a level obtainable from fruit (<10-g/meal) may improve glycemic control in humans.

Objective: To improve evidence-based guidance for fructose recommendations, the investigators propose conducting a series of 7 systematic reviews and meta-analyses of controlled feeding trials to assess the effect of oral fructose on cardiometabolic risk in humans. The first 6 systematic reviews and meta-analyses will each be conducted on a different area of cardiometabolic risk: (1) lipids, (2) glycemic control, (3) body weight, (4) uric acid, (5) blood pressure, and (6) non-alcoholic fatty liver (NAFL). The seventh meta-analysis will investigate the effect of small, "catalytic" doses of fructose at a level obtainable from fruit (<10-g/meal) on all areas of cardiometabolic risk.

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 in isocaloric exchange for other carbohydrate sources (isocaloric trials) or added to a control diet as a source of excess energy (hypercaloric trials) on cardiometabolic risk factors in humans. Studies that are <7-days diet duration, lack a control, or do not provide viable endpoint data will be excluded. To isolate the effects of fructose, we will also exclude trials in which fructose was administered exclusively as sucrose (bound fructose) or high-fructose corn syrup (42% to 55% of free fructose), except where these sweeteners were the comparator.

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 all outcomes. Standard computations and imputations will be used to derive missing variance data. Investigators will assess the quality/validity of each study using the Heyland Methodological Quality Score (MQS).

Outcomes: The first 6 of 7 proposed analyses will each assess a set of outcomes related to a different area of cardiometabolic risk: (1) lipids (fasting lipids [triglycerides, HDL-cholesterol [C], LDL-C, apo-B, total-C:HDL-C ratio, apo-B:apo-A1 ratio, non-HDL-C] and postprandial lipids(non-fasting peak, mean, and area under the curve [AUC] triglycerides), (2) glycemic control (fasting glucose and insulin, glycated blood proteins) and insulin sensitivity (Euglycemic-hyperinsulinemic clamp, frequent sampling intravenous glucose tolerance test [FSIGT], Homeostasis model assessment of insulin resistance [HOMA-IR], oral glucose tolerance test insulin sensitivity index [OGTT-ISI]), (3) body weight, (4) uric acid, (5) blood pressure (systolic BP, diastolic BP, mean arterial pressure), and (6) NAFL (imaging and spectroscopy endpoints of liver fat and biomarkers of hepatocellular injury [transaminases]). The last proposed analysis investigating the effect of small, "catalytic" doses of fructose will focus on all 6 outcomes.

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 according to Elbourne et al. (Int J Epidemiol. 2002;31:140-149). Heterogeneity will be assessed by the Q statistic and quantified by I2. A priori subgroup analyses will be undertaken to explore sources of heterogeneity including the effect of underlying disease status, 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.) and sensitivity analyses. Meta-regression analyses will assess the significance of subgroups analyses with piece-wise meta-regression techniques used to identify dose or follow-up thresholds. 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: A pilot project which explored the effect of fructose on lipids in diabetes identified 786 articles, of which 14 (16 trials)were included in a meta-analysis. Isocaloric exchange of fructose for carbohydrate had a triglyceride raising effect in type 2 diabetes only where the reference carbohydrate was starch, dose was >60-g/d, or follow-up was ≤4-weeks. These distinctions had not been appreciated previously (Sievenpiper et al. Diabetes Care 2009;32:1930-1937).

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

Study Type

Observational

Enrollment (Anticipated)

1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5C 2N8
        • The Toronto 3D (Diet, Digestive tract and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Micheal's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Varied.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Lipid Analysis
Time Frame: June 2012

Analyses:

  1. Fasting lipids (triglycerides, HDL-cholesterol [C], LDL-C, apo-B, total-C:HDL-C ratio, apo-B:apo-A1 ratio, non-HDL-C)
  2. Postprandial lipids (peak, mean, and area under the curve [AUC] triglycerides)
June 2012
Body Weight Analysis
Time Frame: November 2011

Analyses:

1. Body weight
November 2011
Glycemic Control Analysis
Time Frame: June 2012

Analyses:

  1. Glycated blood proteins (HbA1c, fructosamine, glycated albumin), glucose, and insulin in people with diabetes
  2. Glycated blood proteins (HbA1c, fructosamine, glycated albumin), glucose, and insulin in people without diabetes
  3. Insulin sensitivity (Euglycemic-hyperinsulinemic clamp, frequent sampling intravenous glucose tolerance test [FSIGT], Homeostasis model assessment of insulin resistance [HOMA-IR], oral glucose tolerance test insulin sensitivity index [OGTT-ISI])
June 2012
Blood Pressure (BP) Analysis
Time Frame: January 2012

Analyses:

1. Systolic BP, diastolic BP, and mean arterial pressure (MAP)
January 2012
Uric Acid Analysis
Time Frame: February 2012

Analyses:

1. uric acid
February 2012
"Catalytic" Fructose Across Cardiometabolic Endpoints Analysis
Time Frame: January 2012

Analyses:

1. Lipids, glycemic control, body weight, blood pressure, and uric acid
January 2012
Non-Alcoholic Fatty Liver (NAFL) Analysis
Time Frame: June 2012

Analyses:

1. Imaging and spectroscopy endpoints of liver fat (Liver ultrasound [US], computed tomography [CT], magnetic resonance imaging [MRI], or magnetic resonance spectroscopy [MRS]) and biomarkers of hepatocellular injury (transaminases [ALT, AST, GGT])
June 2012

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

John Sievenpiper

Collaborators

Canadian Institutes of Health Research (CIHR)
Canada Research Chairs Endowment of the Federal Government of Canada
Calorie Control Council

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2009

Primary Completion (Actual)

March 1, 2014

Study Completion (Anticipated)

March 1, 2016

Study Registration Dates

First Submitted

May 25, 2011

First Submitted That Met QC Criteria

June 1, 2011

First Posted (Estimate)

June 2, 2011

Study Record Updates

Last Update Posted (Estimate)

May 27, 2015

Last Update Submitted That Met QC Criteria

May 26, 2015

Last Verified

May 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CIHR-KS-2009-205030

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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