Do fructose-containing sugars lead to adverse health consequences? Results of recent systematic reviews and meta-analyses

Do fructose-containing sugars lead to
adverse health consequences?
Results of recent systematic reviews and
meta-analyses
John L Sievenpiper, MD, PhD1,2,3
1
Scientist, Li Ka Shing Knowledge Institute, Toronto, ON, CANADA
2
Knowledge Synthesis Lead
Toronto 3D Knowledge Synthesis and Clinical Trials Unit
Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON, CANADA
3
Resident Physician, Department of Pathology and Molecular Medicine,
Faculty of Health Sciences, McMaster University, Hamilton, ON, CANADA.
Sugars and Health Controversies: What does the science say?
Experimental Biology
San Diego, CA

Disclosures (over past 24 mos)
Board Member/Advisory Panel
–Canadian Diabetes Association (CDA) 2013 Clinical Practice
Guidelines Expert Committee for Nutrition therapy
–European Association for the Study of Diabetes (EASD) 2015
Clinical Practice Guidelines Expert Committee for Nutrition
therapy
–American Society for Nutrition (ASN) writing panel for a
scientific statement on the metabolic and nutritional effects of
fructose, sucrose and high fructose corn syrup
–International Life Science Institute (ILSI) North America,
Food, Nutrition, and Safety Program (FNSP) Advisory Board
–Transcultural Diabetes Algorithm (tDNA) Group
–Diabetes Nutrition Study Group (DNSG) of the European
Association for the Study of Diabetes (EASD) executive
committee
Research Support
–Canadian Institutes of Health Research (CIHR)
–Calorie Control Council
–The Coca Cola Company (**unrestricted, investigator initiated
education grant**)
–Pulse Canada
–International Tree Nut Council Nutrition Research & Education
Foundation
–Dr. Pepper Snapple Group(**unrestricted, investigator
initiated donation**)
Honouria and Speaker fees
–National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) of the National Institutes of health (NIH)
–American College of Physicians (ACP)
–American Society for Nutrition (ASN)
–American Heart Association (AHA)
–Canadian Nutrition Society (CNS)
–Canadian Diabetes Association (CDA)
–International Life Sciences Institute (ILSI) North American
–International Life Sciences Institute (ILSI) Brazil
–Pulse Canada
–Abbott Laboratories
–Calorie Control Council
–The Coca Cola Company
–Canadian Sugar Institute
–Dr. Pepper Snapple Group
Other
–Spouse is an employee of Unilever Canada
–Editorial Board, American Journal of Clinical Nutrition
–Associate Editor, Frontiers in Nutrition, Nutrition Methodology
–Special Issue ("Sugar and Obesity“) Editor, Nutrients

1972
John Yudkin
1964
Ancel Keys
19701952
The great debate: Fat versus sugar

Vuilleumier S.. Am J Clin Nutr 1993;58(suppl):733S–6S.
Flegal KM, et al. JAMA 2002;288:1723–7.
Bray GA, et a. Am J Clin Nutr. 2004 Apr;79(4):537-43
Ecological relationship between fructose intake
and prevalence of Overweight/Obesity:1961-2000
George Bray
2004
Overweight
Obesity
Total fructose
Free fructose
HCFS

Harper's Illustrated Biochemistry, 27th ed, 2006
Fructose as an unregulated substrate for de
novo lipogenesis (DNL)
Phosphofructokinase
Dietary Fructose
Dietary Glucose
Glycerol-3P
Fatty acid
synthesis
↑TAGs

Metabolic fate of fructose in humans:
A review of oral and liver catheterization, stable isotope studies
Sun SZ, Empie MW. Nutr Metab 2012;9:89
DNL <3%
Tappy et al. Physiol Rev. 2010 90:23-46
(<0.198 µmol/L)
(50-100g)

A fructose-centric champion emerges
http://www.youtube.com/watch?v=dBnniua6-oM

A fructose-centric view becomes doctrine
Lustig et al. Nature 2012;482:27-29 http://www.cbsnews.com/video/watch/?

Sugars the new dominant public health issue
http://www.who.int/nutrition/sugars_public_consultation/en

“It is all about fructose” (Bray 2010)
Lustig et al. Nature 2012;482:27-29

http://www.sign.ac.uk/guidelines/fulltext/50/annexb.html
http://www.cnpp.usda.gov/Publications/NutritionInsights/Insight38.pdf
http://www.nice.org.uk/niceMedia/pdf/GDM_Chapter7_0305.pdf
Hierarchy of evidence in evidence based medicine
Systematic
review/
meta-analysis RCTs
RCT
Systematic review/meta-analysis NRCTs
Non-randomized controlled trial (NRCT)
Systematic review/meta-analysis cohort/case-control studies
cohort study/case-control study
Cross-sectional study
Case series/time series
Expert opinion
Decreasing bias

Fructose-containing
Sugar Sweetened Beverages (SSBs)

Fructose-containing Sugar-sweetened beverages
(SSBs) and Incident Cardiometabolic Disease
SSBs
Diabetes/MetS (epi)
Overweight/Obesity (epi)
Hypertension (epi)
Gout (epi)
CHD (epi)
Stroke (epi)

Malik et al. Diabetes Care. 2010 33:2477–2483
Individuals in the highest quantile of SSB intake (most often 1–2 servings/day)
compared with those in the lowest quantile (none or 1 serving/month) had a higher risk
of…
**SSB drinkers in these cohorts consumed more energy, exercised less, and smoked more**
Effect of fructose-containing SSBs on risk of type 2
diabetes and metabolic syndrome:
Meta-analysis of 11 prospective studies (n=310,819)
Risk of Type 2 diabetes Risk of Metabolic syndrome
Adjusted for energy

How do SSBs compare with other risk
factors?

Population attributable mortality risk in the U.S.:
How do SSBs compare with other risk factors?
Danaei et al. PLoS Med 6(4): e1000058. doi:10.1371/journal.pmed.1000058
SSBs
467,000
395,000
216,000
191,000
190,000
102,000
110,000
84,000
82,000
64,000
55,000
15,000
25,000
http://circ.ahajournals.org/cgi/content/meeting_abstract/127/12_MeetingAbstracts/AMP22

Why are SSBs associated with
increased cardiometabolic risk?
1. is it because liquid calories are poorly compensated?
2. is it because SSBs are a maker of an unhealthy lifestyle?
3. Is it the fructose?

Does impaired compensation from liquid calorie
preloads lead to weight gain?
A systematic review and meta-analysis of the
effect of 253 acute preload interventions on
Energy compensation
RCTs of the effect of liquid calories on weight gain
Crossover trial
SSBs vs Jelly beans
N = 15
FU = 4-weeks
∆body weight, P=NS
Crossover trial
Liquid vs solid fruit
N = 34
FU = 8-weeks
∆body weight, P=NS
Almiron-Roig et al. Nutr Rev. 2013 Jul;71(7):458-73
Houchins et al. Obesity. 2012;20:1844-50
DiMeglio et al. Int J Obes. 2000; 24:794-800.

Mozaffarian et al. NEJM 2011;364:2392-2404
+3.35lb
+1.69lb
+0.57lb
+1.00lb
+0.95 lb
+0.28 to 0.36lb
+0.65lb
Increased servings of different foods contribute to
weight change over 4 year intervals:
NHS I (1986-2006), NHS II (1991-2003) and HPFS (1986-2006), N=120 877
+0.93 lb
**Multivariate adjustment for age, BMI, sleep, physical activity, alcohol, television
watching, smoking, and all dietary factors**

A Western Dietary pattern increases diabetes risk more
than any one dietary component:
NHS I (1984-1994, N=35 340) and NHS II (1991-1995, N=89 311)
Schulze et al. Am J Clin Nutr 2005;82:675–84
Western Dietary pattern = high in refined grains, other
vegetables, processed meat , and sugary beverages, diet
soft drinks

Why are SSBs associated with
increased cardiometabolic risk?
1. is it because liquid calories are poorly compensated?
2. is it because SSBs are a maker of an unhealthy lifestyle?
3. Is it the sugar (fructose)?

Meta-analyses of Fructose-containing Sugars and
Incident Cardiometabolic Disease (NCT01608620)
Fructose
Diabetes/MetS (epi)
Overweight/Obesity (epi)
Hypertension (epi)
Gout (epi)
CHD (epi)
(J Am Coll Nutr, in press)

Meta-analyses of Fructose-containing Sugars and
Incident Cardiometabolic Disease (NCT01608620)
Fructose
Diabetes/MetS (epi)

Tsilias et al., unpublished
Consort statement (through May 25, 2012)
Screened: 4642
Included cohorts: 7
4642 reports identified through searching
2694 EMBASE (through to May week 3 2012)
1220 MEDLINE (through to May week 3 2012)
494 CINAHL (through to May week 3 2012)
234 Cochrane Library (through to May week 3 2012)
0 Manual Searches
4597 reports excluded on the basis of title or abstract
1329 duplicate reports
1214 review papers/meta-analyses/editorials/commentaries/letters/
proceedings/practice guidelines/reports
914 other observational studies (including cross-sectional, retrospective
cohort, case control, case report, case series, and ecological)
566 intervention trials
495 animal or in vitro studies
79 studies with irrelevant endpoints
45 reports reviewed in full
41 reports excluded
17 studies with no assessment of fructose-containing sugar exposure
12 review papers/meta-analyses/editorials/commentaries/letters/
proceedings/practice guidelines/reports
3 other observational studies (cross-sectional, retrospective cohort,
case control, case report, case series, and ecological analyses)
3 intervention trials
2 studies with irrelevant endpoints
2 studies with diabetes data not presented
2 non-retrievable studies
4 reports (7 analyses) included in the meta-analysis

Lack of relation of fructose with diabetes risk:
A meta-analysis of prospective cohort studies
(7 cohorts, N=163,132, mean follow-up=6 years)
Tsilias et al., unpublished

Conclusions: Observational studies
1. Prospective cohorts studies have shown significant positive
association between sugary beverages (?added sugars)
and incident obesity, diabetes, gout, CHD, and stroke.
2. These associations, however, are only significant when
comparing the highest with the lowest levels of intake and
do not hold when modeling total fructose or fructose-
containing sugars (with the exception of gout).
3. These data are limited by residual confounding , collinearly
effects, and unexplained heterogeneity between studies.

Isocaloric “substitution trials”= Energy from sugars
substituted for other sources of energy in the diet
Hypercaloric “addition trials”= Energy from sugars
“added” to the diet
Hypocaloric “subtraction trials” = Energy from sugars
“subtracted” from the diet
4 trial designs:
To interpret results, follow the energy…

Isoenergetic exchange of free sugars with other macronutrients
does not affect body weight: WHO-commissioned systematic review
and meta-analysis of 13 RCTs (n=144)
Te Morenga et al. BMJ. 2012;345:e7492

Addition of excess energy from sugars increases weight in adults:
WHO commissioned systematic review and meta-analysis of 30 RCTs

Addition of excess energy from SSBs results in weight gain
proportional to the increase in excess energy:
A systematic review and meta-analysis of 7 RCTs (n=333)
Mattes et al. Obes Rev. 2011;12:346-65
Kaiser et al. Obes Rev. 2013 Jun 7. doi: 10.1111/obr.12048.

Addition of excess energy from SSBs results in weight gain:
A systematic review and meta-analysis of 5 RCTs in adults (n=272)
Malik et al. AJCN. 2013 Oct;98(4):1084-102.

Reduction in energy from sugar reduces excess body fatness in
adults but not children:
WHO commissioned systematic review and meta-analysis of 30 RCTs
Children
Adults

Reduction in energy from SSBs does not affect weight across trials
but leads to less weight gain in overweight/obese subjects:
All subject types
Overweight/obese subset
Mattes et al. Obes Rev. 2011;12:346-65
Kaiser et al. Obes Rev. 2013 Jun 7. doi: 10.1111/obr.12048.

Malik et al. AJCN. 2013 Oct;98(4):1084-102.
Reduction in energy from SSBs may not reduce weight in children:

Sucrose and cardiometabolic risk: Systematic
review of 25 controlled dietary trials
Gibson et al. Crit Rev Food Sci Nutr. 2013;53(6):591-614
“It would appear that a moderate
dietary sucrose intake at levels up
to 25% of energy appears to have
no significant adverse effects on
lipid or carbohydrate metabolism in
normal healthy adults when
substituted for starch, at least in
the medium term (several weeks).”

Isocaloric “substitution trials”= comparisons
are matched for energy with fructose substituted for
other sources of carbohydrate in the diet
Hypercaloric “addition trials”= comparisons are
unmatched for energy with energy from fructose
“added” to the diet
Two trial designs:
To interpret results, follow the energy…

Effect of fructose on metabolic control in humans:
A meta-analysis to provide evidence-based guidance for
future nutrition guidelines development (NCT01363791 )
Fructose
Fasting lipids
Body weight
Glycemic control
Blood pressure
Uric acid
(Diabetes Care 2009;32:1930-7)
(Ann Intern Med 2012;156:291-304)
(Diabetes Care 2012;35:1611-20)
(Hypertension 2012;59:787-95)
(J Nutr 2012;142:916-23)
Postprandial lipids
NAFLD
(Atherosclerosis 2014;232:125-133)
(Eur J Clin Nutr. 2014;68:416-423)

Lack of harm in isocaloric comparisons:
>50 trials (N >1000), dose = 22.5-300g/d, FU = 1-52wk
Benefit Harm
Cardiometabolic endpoint Comparisons N Standardized Mean Difference (SMD) with 95% CI I2
Body weight (22) 31 637 -0.22 (-0.58, 0.13) 37%*
Fasting Lipids (16,159) TG
TC
LDL-C
HDL-C
48
31
20
27
809
569
313
425
0.24 (-0.05, 0.52)
0.30 (-0.05, 0.65)
-0.09 (-0.53, 0.35)
0.38 (0.00, 0.75)
77%*
96%*
100%*
100%*
Postprandial TG (160) 14 290 0.14 (-0.02, 0.30) 54%*
Glycemic control (20,158) GBP
FBG
FBI
19
43
32
276
823
563
-0.28 (-0.45, -0.11)
-0.10 (-0.40, 0.20)
-0.32 (-0.66, 0.03)
50%*
78%*
87%*
Blood pressure (21) SBP
DBP
MAP
13
13
13
352
352
352
-0.39 (-0.93, 0.16)
-0.68 (-1.23, -0.14)
-0.64 (-1.19, -0.10)
31%
47%*
97%*
Uric acid (157) 18 390 0.04 (-0.43, 0.50) 0%
NAFLD (161) IHCL
ALT
4
6
95
164
-0.09 (-0.36, 0.18)
0.07 (-0.73, 0.87)
0%
0%

Harm in hypercaloric trials:
An effect more attributable to energy (up to +250g/d +50% E)
Benefit Harm
Cardiometabolic endpoint Comparisons N Standardized Mean Difference (SMD) with 95% CI I2
Body weight (22) 10 119 1.24 (0.61, 1.85) 30%
Fasting lipids (16,159) TG
TC
LDL-C
HDL-C
7
5
4
4
122
102
95
79
1.05 (0.31, 1.79)
0.39 (-0.50, 1.25)
0.22 (-0.77, 1.19)
0.00 (0.00, 0.00)
87%*
89%*
96%*
100%*
Postprandial TG (160) 2 32 0.65 (0.30, 1.01) 22%
Glycemic control (20,158) GBP
FBG
FBI
2
8
8
31
98
98
-0.33 (-0.62, -0.04)
1.32 (0.63, 2.02)
0.95 (0.26, 1.64)
0%
59%*
41%
Blood pressure (21) MAP 2 24 -0.76 (-2.15, 0.62) 24%
Uric acid (157) 3 35 2.26 (1.13, 3.39) 0%
NAFLD (161) IHCL
ALT
5
4
60
59
0.45(0.18, 0.72)
0.99 (0.01, 1.97)
51%*
28%

Conclusions: Trials
1. There is a moderate body of consistent evidence from controlled feeding trials
that fructose at low to moderate doses does not harm body weight, serum
fasting or postprandial lipids, uric acid, and NAFLD and may even benefit
blood pressure and glycemic control in humans.
2. There is an emerging body of consistent evidence from controlled feeding trials
that fructose consumed under hypercaloric feeding conditions may promote
weight gain, fasting and postprandial dyslipidemia, raised uric acid levels,
and NAFLD, effects which appear more attributable to the excess energy
than the fructose itself.
3. The shorter duration, poor quality and heterogeneity in the available trials
creates some uncertainty about the true effects of fructose. There is a need for
larger, longer-term, higher quality “real world” feeding trials to guide our
understanding of the metabolic effects of fructose.

Take away message
1. Like with the earlier fat story, it is difficult to separate the
contribution of fructose-containing sugars from that of other
factors in the epidemic of obesity and cardiometabolic disease,
owing to the small effect sizes and lack of demonstrated harm
over other sources of excess energy in the diet
2. There are many pathways to overconsumption leading to weight
gain and its downstream consequences. Dietary patterns have
the greatest influence on weight gain and cardiometabolic risk
and represent the best opportunity for successful interventions.
3. Attention needs to remain focused on reducing overconsumption
of all caloric foods (including sugary beverages and foods!)
and promoting greater physical activity.

Acknowledgements
Arash Mirrahimi, HBSc, MSc (Coordinator, Co-I)
Amanda J Carleton, MSc (MD student, Co-P)
Dr. Sonia Blanco MD, MSc (Coordinator)
Laura Chiavaroli, MSc (PhD Candidate)
Adrian I Cozma, HBSc (Research Assistant)
Vanessa Ha, HBSc (MSc Candidate)
David Wang, HBSc (Project Student)
Simon Chiu (Project Student)
Matt E Yu, HBSc (Project Student)
Viranda (Jay) Jayalath (Project Student)
Christine Tsilias (Project Student)
Reem Tawfik (Project Student)
Sara Rehman (Project Student)
Vivian Choo (Project Student)
Dr. Alexandra L Jenkins, PhD, RD (Decision Maker)
Prof. Lawrence A Leiter, MD (Decision Maker)
Prof. Thomas MS Wolever, MD, PhD (Decision Maker)
Dr. Russell J de Souza, ScD, RD (PDF, Co-I)
Dr. Marco DiBuono, PhD (Decision Maker)
Prof. Joseph Beyene, PhD (Co-I)
Prof. David JA Jenkins MD, PhD, DSc (PI) Prof. Cyril WC Kendall, PhD (Co-I)

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