Meta-Analysis

. 2015 Sep 10;4(9):e001700.

doi: 10.1161/JAHA.114.001700.

Effect of Fructose on Established Lipid Targets: A Systematic Review and Meta-Analysis of Controlled Feeding Trials

Laura Chiavaroli¹, Russell J de Souza², Vanessa Ha², Adrian I Cozma¹, Arash Mirrahimi³, David D Wang⁴, Matthew Yu⁵, Amanda J Carleton⁶, Marco Di Buono⁷, Alexandra L Jenkins⁸, Lawrence A Leiter⁹, Thomas M S Wolever¹⁰, Joseph Beyene¹¹, Cyril W C Kendall¹², David J A Jenkins⁹, John L Sievenpiper¹³

Affiliations

¹ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.).
² Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada (R.J.S., V.H., J.B.).
³ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) School of Medicine, Faculty of Health Sciences, Queen's University, Kingston, ON, Canada (A.M.).
⁴ Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.).
⁵ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) School of Dentistry, University of Minnesota, Minneapolis, MN (M.Y.).
⁶ Department of Undergraduate Medical Education (MD Program), Faculty of Medicine, University of Toronto, ON, Canada (A.J.C.).
⁷ Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Heart and Stroke Foundation of Ontario, Toronto, ON, Canada (M.D.B.) American Heart Association, Dallas, TX (M.D.B.).
⁸ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.).
⁹ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Division of Endocrinology, St. Michael's Hospital, Toronto, ON, Canada (L.A.L., T.S.W., D.A.J., J.L.S.) Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada (L.A.L., D.A.J., J.L.S.) Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Department of Medicine, Faculty of Medicine, University of Toronto, ON, Canada (L.A.L., T.S.W., D.A.J.).
¹⁰ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Division of Endocrinology, St. Michael's Hospital, Toronto, ON, Canada (L.A.L., T.S.W., D.A.J., J.L.S.) Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Department of Medicine, Faculty of Medicine, University of Toronto, ON, Canada (L.A.L., T.S.W., D.A.J.).
¹¹ Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada (R.J.S., V.H., J.B.).
¹² Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada (C.C.K.).
¹³ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Division of Endocrinology, St. Michael's Hospital, Toronto, ON, Canada (L.A.L., T.S.W., D.A.J., J.L.S.) Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada (L.A.L., D.A.J., J.L.S.) Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada (J.L.S.).

PMID: 26358358
PMCID: PMC4599489
DOI: 10.1161/JAHA.114.001700

Meta-Analysis

Effect of Fructose on Established Lipid Targets: A Systematic Review and Meta-Analysis of Controlled Feeding Trials

Laura Chiavaroli et al. J Am Heart Assoc. 2015.

. 2015 Sep 10;4(9):e001700.

doi: 10.1161/JAHA.114.001700.

Authors

Affiliations

¹ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.).
² Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada (R.J.S., V.H., J.B.).
³ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) School of Medicine, Faculty of Health Sciences, Queen's University, Kingston, ON, Canada (A.M.).
⁴ Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.).
⁵ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) School of Dentistry, University of Minnesota, Minneapolis, MN (M.Y.).
⁶ Department of Undergraduate Medical Education (MD Program), Faculty of Medicine, University of Toronto, ON, Canada (A.J.C.).
⁷ Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Heart and Stroke Foundation of Ontario, Toronto, ON, Canada (M.D.B.) American Heart Association, Dallas, TX (M.D.B.).
⁸ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.).
⁹ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Division of Endocrinology, St. Michael's Hospital, Toronto, ON, Canada (L.A.L., T.S.W., D.A.J., J.L.S.) Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada (L.A.L., D.A.J., J.L.S.) Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Department of Medicine, Faculty of Medicine, University of Toronto, ON, Canada (L.A.L., T.S.W., D.A.J.).
¹⁰ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Division of Endocrinology, St. Michael's Hospital, Toronto, ON, Canada (L.A.L., T.S.W., D.A.J., J.L.S.) Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Department of Medicine, Faculty of Medicine, University of Toronto, ON, Canada (L.A.L., T.S.W., D.A.J.).
¹¹ Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada (R.J.S., V.H., J.B.).
¹² Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada (C.C.K.).
¹³ Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, ON, Canada (L.C., R.J.S., V.H., A.I.C., A.M., M.Y., A.L.J., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Division of Endocrinology, St. Michael's Hospital, Toronto, ON, Canada (L.A.L., T.S.W., D.A.J., J.L.S.) Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada (L.A.L., D.A.J., J.L.S.) Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, ON, Canada (L.C., A.I.C., D.D.W., M.D.B., L.A.L., T.S.W., C.C.K., D.A.J., J.L.S.) Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada (J.L.S.).

PMID: 26358358
PMCID: PMC4599489
DOI: 10.1161/JAHA.114.001700

Abstract

Background: Debate over the role of fructose in mediating cardiovascular risk remains active. To update the evidence on the effect of fructose on established therapeutic lipid targets for cardiovascular disease (low-density lipoprotein cholesterol [LDL]-C, apolipoprotein B, non-high-density lipoprotein cholesterol [HDL-C]), and metabolic syndrome (triglycerides and HDL-C), we conducted a systematic review and meta-analysis of controlled feeding trials.

Methods and results: MEDLINE, EMBASE, CINHAL, and the Cochrane Library were searched through July 7, 2015 for controlled feeding trials with follow-up ≥7 days, which investigated the effect of oral fructose compared to a control carbohydrate on lipids (LDL-C, apolipoprotein B, non-HDL-C, triglycerides, and HDL-C) in participants of all health backgrounds. Two independent reviewers extracted relevant data. Data were pooled using random effects models and expressed as mean difference with 95% CI. Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I(2) statistic). Eligibility criteria were met by 51 isocaloric trials (n=943), in which fructose was provided in isocaloric exchange for other carbohydrates, and 8 hypercaloric trials (n=125), in which fructose supplemented control diets with excess calories compared to the control diets alone without the excess calories. Fructose had no effect on LDL-C, non-HDL-C, apolipoprotein B, triglycerides, or HDL-C in isocaloric trials. However, in hypercaloric trials, fructose increased apolipoprotein B (n=2 trials; mean difference = 0.18 mmol/L; 95% CI: 0.05, 0.30; P=0.005) and triglycerides (n=8 trials; mean difference = 0.26 mmol/L; 95% CI: 0.11, 0.41; P<0.001). The study is limited by small sample sizes, limited follow-up, and low quality scores of the included trials.

Conclusions: Pooled analyses showed that fructose only had an adverse effect on established lipid targets when added to existing diets so as to provide excess calories (+21% to 35% energy). When isocalorically exchanged for other carbohydrates, fructose had no adverse effects on blood lipids. More trials that are larger, longer, and higher quality are required.

Clinical trials registration: URL: https://www.clinicaltrials.gov/. Unique Identifier: NCT01363791.

Keywords: lipids; meta‐analysis; nutrition.

PubMed Disclaimer

Figures

**Figure 2**
Forest plots of the effect of fructose on LDL-C in isocaloric feeding trials. Pooled effect estimates are shown as diamonds. Data are expressed as MD with 95% CI using generic inverse variance random effects models. Interstudy heterogeneity was tested the Cochran Q statistic at a significance level of P<0.10 and quantified by the I² statistic, where I²≥50% is considered to be evidence of substantial heterogeneity and ≥75% considerable heterogeneity. Any CHO denotes any carbohydrate comparator. HTG indicates hypertriglyceridemic; LDL-C, low density lipoprotein; MD, mean difference.

**Figure 3**
Forest plots of the effect of fructose on apo B in isocaloric feeding trials. Pooled effect estimates are shown as diamonds. Data are expressed as MD with 95% CI using generic inverse variance random effects models. Interstudy heterogeneity was tested by the Cochran Q statistic at a significance level of P<0.10 and quantified by the I² statistic, where I²≥50% is considered to be evidence of substantial heterogeneity and ≥75% considerable heterogeneity. Any CHO denotes any carbohydrate comparator. apo B indicates apolipoprotein B; HTG, hypertriglyceridemic; MD, mean difference.

**Figure 4**
Forest plots of the effect of fructose on non-HDL-C in isocaloric feeding trials. Pooled effect estimates are shown as diamonds. Data are expressed as MD with 95% CI using generic inverse variance random effects models. Interstudy heterogeneity was tested by the Cochran Q statistic at a significance level of P<0.10 and quantified by the I² statistic, where I²≥50% is considered to be evidence of substantial heterogeneity and ≥75% considerable heterogeneity. Any CHO denotes any carbohydrate comparator. HDL-C indicates high density lipoprotein; HTG, hypertriglyceridemic; MD, mean difference; T2DM, type 2 diabetes mellitus.

**Figure 5**
Forest plots of the effect of fructose on triglycerides in isocaloric feeding trials. Pooled effect estimates are shown as diamonds. Data are expressed as MD with 95% CI using generic inverse variance random effects models. Inter-study heterogeneity was tested by the Cochran Q statistic at a significance level of P<0.10 and quantified by the I² statistic, where I²≥50% is considered to be evidence of substantial heterogeneity and ≥75% considerable heterogeneity. A, B refers to study A and study B (two separate trials) within the same report. Any CHO denotes any carbohydrate comparator. HTG indicates hypertriglyceridemic; MD, mean difference.

**Figure 6**
Forest plots of the effect of fructose on HDL-C in isocaloric feeding trials. Pooled effect estimates are shown as diamonds. Data are expressed as MD with 95% CI using generic inverse variance random effects models. Interstudy heterogeneity was tested by the Cochran Q statistic at a significance level of P<0.10 and quantified by the I² statistic, where I²≥50% is considered to be evidence of substantial heterogeneity and ≥75% considerable heterogeneity. Any CHO denotes any carbohydrate comparator. HDL-C indicates high density lipoprotein; HTG, hypertriglyceridemic; MD, mean difference.

**Figure 7**
Forest plots of the effect of fructose on apo B in hypercaloric feeding trials. Pooled effect estimates are shown as diamonds. Data are expressed as MD with 95% CI using generic inverse variance random effects models. Interstudy heterogeneity was tested by the Cochran Q statistic at a significance level of P<0.10 and quantified by the I² statistic, where I²≥50% is considered to be evidence of substantial heterogeneity and ≥75% considerable heterogeneity. Any CHO denotes any carbohydrate comparator. apo B indicates apolipoprotein B; MD, mean difference.

**Figure 8**
Forest plots of the effect of fructose on triglycerides in hypercaloric feeding trials. Pooled effect estimates are shown as diamonds. Data are expressed as mean difference with 95% CI using generic inverse variance random effects models. Interstudy heterogeneity was tested by the Cochran Q statistic at a significance level of P<0.10 and quantified by the I² statistic, where I²≥50% is considered to be evidence of substantial heterogeneity and ≥75% considerable heterogeneity. Any CHO denotes any carbohydrate comparator.

See this image and copyright information in PMC

References

1. Lustig RH. Fructose: metabolic, hedonic, and societal parallels with ethanol. J Am Diet Assoc. 2010;110:1307–1321. - PubMed
1. Goran MI, Ulijaszek SJ, Ventura EE. High fructose corn syrup and diabetes prevalence: a global perspective. Glob Public Health. 2013;8:55–64. - PubMed
1. Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, Lennie TA, Levi M, Mazzone T, Pennathur S American Heart Association Clinical Lipidology T, Prevention Committee of the Council on Nutrition PA, Metabolism, Council on Arteriosclerosis T, Vascular B, Council on Cardiovascular N, Council on the Kidney in Cardiovascular Disease. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123:2292–2333. - PubMed
1. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2013 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2013;37(suppl 1):S1–S212. - PubMed
1. Livesey G, Taylor R. Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies. Am J Clin Nutr. 2008;88:1419–1437. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov

Grants and funding

102078/Canadian Institutes of Health Research/Canada

LinkOut - more resources

Full Text Sources
Medical
- ClinicalTrials.gov
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Effect of Fructose on Established Lipid Targets: A Systematic Review and Meta-Analysis of Controlled Feeding Trials

Affiliations

Effect of Fructose on Established Lipid Targets: A Systematic Review and Meta-Analysis of Controlled Feeding Trials

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous