sugars, obesity, and cardiometabolic...

Sugars, Obesity, and

Cardiometabolic risk

John L Sievenpiper, MD, PhD, FRCPC1,2,3,4

1Consultant Physician, Division of Endocrinology, St. Michael’s Hospital, University of Toronto

2Scientist, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto

3Knowledge Synthesis Lead, Toronto 3D Knowledge Synthesis & Clinical Trials Unit,

St. Michael’s Hospital, University of Toronto

Advances & Controversies in Clinical Nutrition

Controversy Session: Sugars and Health: Are we winning the battle, but

losing the war”

National Harbor, MD

December 4-6, 2014

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 sugars

–International Life Science Institute (ILSI) North America, Food,

Nutrition, and Safety Program (FNSP) Advisory Panel

–Transcultural Diabetes Algorithm (tDNA) Group

–Diabetes Nutrition Study Group (DNSG) of the European

Association for the Study of Diabetes (EASD) Board

Research Support

–American Society of Nutrition (ASN)

–Canadian Institutes of Health Research (CIHR)

–Calorie Control Council

–The Coca Cola Company (unrestricted, investigator initiated)

–Pulse Canada

–International Tree Nut Council Nutrition Research & Education

Foundation

–Dr. Pepper Snapple Group (unrestricted, investigator initiated)

Consulting Arrangements

–Tate & Lyle

–Winston Strawn LLP

–Perkins Coie LLP

Honouria or Speaker fees

–American Society of Nutrition (ASN)

–National Institutes of health (NIH)

–American College of Physicians (ACP)

–American Heart Association (AHA)

–Canadian Nutrition Society (CNS)

–Canadian Diabetes Association (CDA)

–University of Alabama at Birmingham

–University of South Carolina

–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

–Dairy Farmers of Canada

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

1.Understand the role of fructose’s unique biochemistry,

metabolism, and endocrine responses

2.Assess the evidence from prospective cohort studies

linking fructose-containing sugars with obesity

3.Discuss the role of energy in the effect of sugars on

weight gain in controlled trials

OBJECTIVES

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

A “Canadian Paradox” – estimated sugar intake has

decreased while obesity has increased: Canadian Community Health Survey (CCHS), National Population Health

Survey (NPHS), & Statistics Canada

Brisbois TD et al. Nutrients. 2014;6:1899-912.

http://www.statcan.gc.ca/pub/82-003-x/2011003/article/11540-eng.pdf

Total sugars = 21%

(added sugars = 11%)

Ecological relation of water intake with

prevalence of Overweight/Obesity: 1961-2000

Kaiser et al. Obes Rev. 2013 Jun 7. doi: 10.1111/obr.12048.

Fructose as an unregulated substrate for de

novo lipogenesis (DNL)

A sugar (fructose)-centric view of

cardiometabolic disease emerges

Sugars the new dominant public health issue: WHO proposed update to sugars recommendations

http://www.who.int/nutrition/sugars_public_consultation/en/

Important caveats…

1.Recommendations were based

exclusively on dental caries and

body weight

2.The body weight effects are

“mediated via changes in energy

intakes”

3.The 10% & 5%

recommendations were based

exclusively on dental caries

4.The 5% recommendation was

based on “very low quality”

evidence

What is the

evidence?

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

Reviews &

meta-analyses

RCTs

Non-randomized controlled trials (NRCT)

Cohorts studies

Case-control studies

Cross-sectional studies

Case series/time series

Expert opinion

Decreasing bias




PROSPECTIVE

COHORTS

What about

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) Important caveats…

1. Relationship only seen in extreme quantiles analyses with few exceptions

2. Associations lose significance or are greatly attenuated by adjustement for energy

3. Residual confounding from important collinearity: high consumers eat more

calories, exercise less, smoke more, and have a poorer dietary pattern

How do SSBs compare with other risk

factors?

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**

Mozaffarian et al. NEJM 2011;364:2392-2404

-0.22lb

-0.49lb

-0.57lb

-0.82lb

-0.37lb

-0.11lb

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

**Multivariate adjustment for age, BMI, sleep, physical activity, alcohol, television

watching, smoking, and all dietary factors**

Population attributable burden of disease for 20

leading risk factors in North America in 2010: How do SSBs compare with other risk factors?

Lim et al. Lancet 2012; 380: 2224–60

Why are SSBs associated with

increased obesity cardiometabolic risk?

1. is it because liquid calories are poorly compensated?

2. is it because SSBs are a marker of an unhealthy lifestyle?

3. Is it the sugars (fructose)?

Meta-analyses of Fructose-containing Sugars and

Incident Cardiometabolic Disease (NCT01608620)

Sugars

Diabetes risk

Gout risk

Weight change

Hypertension risk

CHD (epi)

(Jaylath et al. J Am Coll Nutr, in press)



Sugars

Weight change

Kim et al., unpublished

Consort statement (through Jan 17, 2014)

Screened: 1076

Included cohorts:

2 (n=32,405)

Reports identified through searching (n=1076) MEDLINE (through January 17 2014): 336 EMBASE (through January 17 2014): 735 Cochrane Library (through January 17 2014): 3 Manual searches: 2

Reports excluded based on title or abstract (n=1003) Duplicate reports: 241 Animal or in vitro studies: 23 Case control studies: 4 Case studies: 17 Children: 133 Cross sectional studies: 14 Experimental trial: 64 Meta-analyses: 1 Published abstract: 7 Retrospective analysis: 66 Review papers: 38 Studies with no fructose-containing sugar: 359 Studies with unsuitable endpoints: 36

Reports reviewed in full (n=73)

Reports excluded (n=71) Children: 3 Experimental trial: 3 Studies with no fructose-containing sugar: 18 Studies with unsuitable endpoints: 47

Reports meeting criteria (n=2)

Lack of relation of total sugars with weight gain:

A systematic review and meta-analysis of 2 cohorts (n=32,405)

Relative Risk: 0.04 (-0.06, 0.14) p = 0.35

Study or Subgroup

Parker et al 1997

Colditz et al 1990

Total (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 0.19, df = 1 (P = 0.66); I² = 0%

Test for overall effect: Z = 0.76 (P = 0.44)

Weight

0.8%

99.2%

100.0%

IV, Random, 95% CI

-0.20 [-1.28, 0.88]

0.04 [-0.06, 0.14]

0.04 [-0.06, 0.14]

Difference in highest and lowest intake changes Difference in highest and lowest intake changes

IV, Random, 95% CI

-2 -1 0 1 2

Reduced body weight Increased body weight


Consort statement (through Jan, 2014)

Screened:425

Included cohorts:

7 (n=13,400)


Reports identified through searching (n=425) MEDLINE (through May 27 2014): 162 EMBASE (through May 27 2014): 260 Cochrane Library (through May 27 2014): 0 Manual searches: 3

Reports excluded based on title or abstract (n=380) Duplicate reports: 118 Animal or in vitro studies: 1 Case studies: 12 Children: 57 Cross sectional studies: 1 Experimental trial: 28 Published abstract: 1 Retrospective analysis: 10 Review papers: 14 Studies with no sweet foods: 102 Studies with unsuitable endpoints: 36

Reports reviewed in full (n=45)

Reports excluded (n=42) Children: 3 Cross sectional studies: 5 Duplicate reports: 1 Experimental trial: 3 Published abstract: 3 Retrospective studies: 1 Review papers: 1 Studies with no sweet foods: 7 Studies with unsuitable endpoints: 18 Reports meeting criteria (n=3)

Lack of relation of sweets with weight gain:

A systematic review and meta-analysis of 13 cohorts (n=13,400)

Relative Risk: -0.00 (-0.03, 0.03) p = 0.69


French et al. 1997 (F)

French et al. 1997 (M)

Hendriksen et al. 2011 (sweets A&M)

Hendriksen et al. 2011 (cakes A&M)

Hendriksen et al. 2011 (sweets Doetinchem)

Hendriksen et al. 2011 (cakes Doetinchem)

Parker et al. 1997



Sugars

Diabetes risk

Gout risk

Weight change

Hypertension risk

CHD (epi)

(Jaylath et al. J Am Coll Nutr, in press)




Hierarchy of evidence in evidence based medicine

Systematic

Reviews &

meta-analyses

RCTs

Non-randomized controlled trials (NRCT)

Cohorts studies

Case-control studies

Cross-sectional studies

Case series/time series

Expert opinion

Decreasing bias




CONTROLLED DIETARY TRIALS

Is it all about the fructose?

“Substitution trials”= comparisons are matched

for energy with fructose substituted for other sources of

carbohydrate in the diet

“Addition trials”= comparisons are unmatched for

energy with energy from fructose “added” to the diet

2 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) ‘Ca

taly

tic

’ f

ructo

se &

card

iom

eta

bo

lic r

isk

(Br

J N

utr

, 2

01

2;1

08:4

18

-23

)



Fructose

Body weight

(Ann Intern Med 2012;156:291-304)

Sievenpiper et al. Ann Intern Med, 2012

Consort statement (Updated Nov 18, 2011)

Screened: 1984

Isocaloric trials:

31 trials, N=637

Hypercaloric trials:

10 trials, N=119

“Substitution trials”

Effect of fructose on body weight in isocaloric trials:

31 trials (n=637), dose=69-g/d [30-300-g/d]), FU=4-wk(1-52-wk)

Favors fructose

Study or Subgroup

8.1.1 Diabetes

Pelkonen et al.[30]

Mcateer et al. [31]

Osei et al. [32]

Grigoresco et al. [33]

Thorburn et al.[34]

Anderson et al. [35]

Osei and Bosetti [36]

Thorburn et al. [37]

Blayo et al. [38]

Bantle et al. [39]

Koivisto et al. [40]

Malerbi et al. [41]

Vaisman et al. [42]Subtotal (95% CI)



8.1.2 Overweight/obese

Rizkalla et al. [43] (T1)


Swarbrick et al. [44]

Stanhope et al. [45]

Madero et al. [46]Subtotal (95% CI)



8.1.3 Normal-weight

Kaufmann et al. [47]

Forster et al. [48]

Turner et al. [49] (LC)

Turner et al. [49] (HC)

Beck-Nielsen et al. [50]

Swanson et al. [51]

Bantle et al. [52]

Ngo Sock et al. [53]

Aeberli et al. [54] (HD)

Silbernagel et al. [56]


Aeberli et al. [54] (LD)

Brymora et al. [55]Subtotal (95% CI)



Total (95% CI)



Test for subgroup differences: Chi² = 8.58, df = 2 (P = 0.01), I² = 76.7%

Weight

4.8%

6.9%

0.1%

1.8%

0.0%

2.6%

0.7%

1.8%

3.3%

2.6%

1.9%

3.3%

0.1%29.9%

2.1%

2.8%

4.4%

6.2%

5.2%20.8%

4.5%

0.6%

1.8%

1.6%

0.1%

3.8%

5.7%

5.9%

7.1%

1.7%

3.9%

6.8%

5.7%49.4%

100.0%

IV, Random, 95% CI

-0.25 [-1.01, 0.51]

0.20 [-0.30, 0.70]

0.80 [-6.92, 8.52]

-0.10 [-1.62, 1.42]

0.10 [-23.24, 23.44]

2.05 [0.84, 3.25]

2.50 [-0.04, 5.04]

-0.50 [-2.02, 1.02]

0.17 [-0.85, 1.20]

-0.20 [-1.41, 1.01]

-0.90 [-2.38, 0.58]

-0.35 [-1.38, 0.68]

0.00 [-6.93, 6.93]0.12 [-0.32, 0.56]

-0.06 [-1.45, 1.33]

0.35 [-0.79, 1.49]

-1.10 [-1.91, -0.29]

-0.30 [-0.88, 0.28]

-1.13 [-1.83, -0.43]-0.55 [-1.09, -0.02]

-0.18 [-0.97, 0.62]

-0.35 [-3.13, 2.43]

0.40 [-1.11, 1.91]

-0.10 [-1.75, 1.55]

0.60 [-5.91, 7.11]

1.10 [0.18, 2.02]

0.10 [-0.54, 0.74]

-0.40 [-1.01, 0.21]

-0.20 [-0.69, 0.29]

-1.50 [-3.05, 0.05]

-0.50 [-1.39, 0.39]

-0.30 [-0.82, 0.22]

0.00 [-0.64, 0.64]-0.13 [-0.37, 0.10]

-0.14 [-0.37, 0.08]

Year

1972

1987

1987

1988

1989

1989

1989

1990

1990

1992

1993

1996

2006

1986

1986

2008

2009

2011

1966

1973

1979

1979

1980

1992

2000

2010

2011

2011

2011

2011

2011

Mean Difference Mean Difference

IV, Random, 95% CI

-4 -2 0 2 4Favours fructose Favours any CHO

Study or Subgroup Year N

(any CHO)

N

(fructose)

Mean difference (95% CI) in weight (kg)

Diabetes

Pelkonen et al. [30]

Mcateer et al. [31]

Osei et al.[32]






Blayo et al. [38]

Bantle et al. [39]


Malerbi et al. [41]

Vaisman et al. [42]

Subtotal

1972

1987

1987

1988

1989

1989

1989

1990

1990

1992

1993

1996

2006

8

10

9

8

13

14

8

6

14

18

10

16

13

8

10

9

8

13

14

8

6

6

18

10

16

12

-0.25 [-1.01, 0.51]

0.20 [-0.30, 0.70]

0.80 [-6.92, 8.52]

-0.10 [-1.62, 1.42]

2.50 [-0.04, 5.04]

2.05 [0.84, 3.25]

0.10 [-23.24, 23.44]

-0.50 [-2.02, 1.02]

0.17 [-0.85, 1.20]

-0.20 [-1.41, 1.01]

-0.90 [-2.38, 0.58]

-0.35 [-1.38, 0.68]

0.00 [-6.93, 6.93]]

0.12 [-0.32, 0.56]

Hetrerogeneity: Tau2 = 0.18; Chi2 = 17.78, df = 12 (P=0.12), I2 = 33%


Overweight/obese



Swarbrick et al.[44]

Stanhope et al.[45]

Madero et al. [46]

Subtotal

1986

1986

2008

2009

2011

15

12

7

15

66

8

6

7

17

65

-0.06 [-1.45, 1.33]

0.35 [-0.79, 1.49]

-1.10 [-1.91, -0.29]

-0.30 [-0.88, 0.28]

-1.13 [-1.83, -0.43]

-0.55 [-1.09, -0.02]



Normal-weight


Forster et al. [48]




Swanson et al. [51]

Bantle et al. [52]






Brymora et al. [55]

Subtotal

1966

1973

1979

1979

1980

1992

2000

2010

2011

2011

2011

2011

2011

9

12

6

5

7

14

24

11

29

10

32

29

28

9

12

6

5

8

14

24

11

29

10

16

29

28

-0.18 [-0.97, 0.62]

-0.35 [-3.13, 2.43]

0.40 [-1.11, 1.91]

-0.10 [-1.75, 1.55]

0.60 [-5.91, 7.11]

1.10 [0.18, 2.02]

0.10 [-0.54, 0.74]

-0.40 [-1.01, 0.21]

-0.20 [-0.69, 0.29]

-1.50 [-3.05, 0.05]

-0.50 [-1.39, 0.39]

-0.30 [-0.82, 0.22]

0.00 [-0.64, 0.64]

-0.13 [-0.37, 0.10]



Total -0.14 [-0.37, 0.08]




(any CHO)

N

(fructose)


Diabetes

Pelkonen et al. [30]

Mcateer et al. [31]

Osei et al.[32]






Blayo et al. [38]

Bantle et al. [39]


Malerbi et al. [41]

Vaisman et al. [42]

Subtotal

1972

1987

1987

1988

1989

1989

1989

1990

1990

1992

1993

1996

2006

8

10

9

8

13

14

8

6

14

18

10

16

13

8

10

9

8

13

14

8

6

6

18

10

16

12

-0.25 [-1.01, 0.51]

0.20 [-0.30, 0.70]

0.80 [-6.92, 8.52]

-0.10 [-1.62, 1.42]

2.50 [-0.04, 5.04]

2.05 [0.84, 3.25]

0.10 [-23.24, 23.44]

-0.50 [-2.02, 1.02]

0.17 [-0.85, 1.20]

-0.20 [-1.41, 1.01]

-0.90 [-2.38, 0.58]

-0.35 [-1.38, 0.68]

0.00 [-6.93, 6.93]]

0.12 [-0.32, 0.56]

Hetrerogeneity: Tau2 = 0.18; Chi2 = 17.78, df = 12 (P=0.12), I2 = 33%


Overweight/obese



Swarbrick et al.[44]

Stanhope et al.[45]

Madero et al. [46]

Subtotal

1986

1986

2008

2009

2011

15

12

7

15

66

8

6

7

17

65

-0.06 [-1.45, 1.33]

0.35 [-0.79, 1.49]

-1.10 [-1.91, -0.29]

-0.30 [-0.88, 0.28]

-1.13 [-1.83, -0.43]

-0.55 [-1.09, -0.02]



Normal-weight


Forster et al. [48]




Swanson et al. [51]

Bantle et al. [52]






Brymora et al. [55]

Subtotal

1966

1973

1979

1979

1980

1992

2000

2010

2011

2011

2011

2011

2011

9

12

6

5

7

14

24

11

29

10

32

29

28

9

12

6

5

8

14

24

11

29

10

16

29

28

-0.18 [-0.97, 0.62]

-0.35 [-3.13, 2.43]

0.40 [-1.11, 1.91]

-0.10 [-1.75, 1.55]

0.60 [-5.91, 7.11]

1.10 [0.18, 2.02]

0.10 [-0.54, 0.74]

-0.40 [-1.01, 0.21]

-0.20 [-0.69, 0.29]

-1.50 [-3.05, 0.05]

-0.50 [-1.39, 0.39]

-0.30 [-0.82, 0.22]

0.00 [-0.64, 0.64]

-0.13 [-0.37, 0.10]



Total -0.14 [-0.37, 0.08]


Test for overall effect: Z = 1.25 (P = 0.21)Favors fructose Favors any CHO


(matched overfeeding)

Positive energy balance in isocaloric trials

A. Body weight (kg)

Study MD (95%CI)

Beck-Nielsen et al. 1980 [42]

Stanhope et al. 2009 [43]

Ngo Sock et al. 2010 [44]

Silbernagel et al. 2011 [45]


Total (95% CI)

Heterogeneity: (P = 0.71); I² = 0%

Test for overall effect: (P = 0.02)

A. Body weight (kg)

Study MD (95%CI)

Beck-Nielsen et al. 1980 [42]


Ngo Sock et al. 2010 [44]

Silbernagel et al. 2011 [45]


Total (95% CI)

Heterogeneity: (P = 0.71); I² = 0%

Test for overall effect: (P = 0.02)

Study or Subgroup

Beck-Nielsen et al. 1980

Stanhope et al.2009

Ngo Sock et al. 2010

Silbernagel et al. 2011

Stanhope et al. 2011

Total (95% CI)



Weight

0.3%

40.8%

36.1%

5.7%

17.1%

100.0%

IV, Random, 95% CI

0.60 [-5.91, 7.11]

-0.30 [-0.88, 0.28]

-0.40 [-1.01, 0.21]

-1.50 [-3.05, 0.05]

-0.50 [-1.39, 0.39]

-0.44 [-0.80, -0.07]

Year

1980

2009

2010

2011

2011


IV, Random, 95% CI

-4 -2 0 2 4Favours fructose Favours glucose

“Addition trials”

Effect of fructose on weight in hypercaloric (+18-97%E) trials:

10 trials (n=119), dose=+182g/d (+100-250g/d) FU=1.5wk(1-10wk)

Study or Subgroup

5.2.1 Overweight/obese

Rizkalla et al. [58]


Subtotal (95% CI)


Test for overall effect: Z = 4.44 (P < 0.00001)

5.2.2 Normal-weight


Le et al. [59]

Le et al. [60] (N)

Le et al. [60] (ODM2)


Sobrecases et al. [61]



Subtotal (95% CI)



Total (95% CI)



Test for subgroup differences: Chi² = 8.51, df = 1 (P = 0.004), I² = 88.2%

Weight

4.4%

12.0%

16.5%

5.5%

8.3%

12.7%

3.9%

15.0%

24.6%

4.5%

9.0%

83.5%

100.0%

IV, Random, 95% CI

1.10 [-0.08, 2.28]

1.30 [0.67, 1.93]

1.26 [0.70, 1.81]

0.50 [-0.54, 1.54]

0.20 [-0.61, 1.01]

0.60 [-0.00, 1.20]

1.00 [-0.26, 2.26]

0.60 [0.07, 1.13]

0.30 [-0.01, 0.61]

0.20 [-0.98, 1.38]

-0.10 [-0.87, 0.67]

0.37 [0.16, 0.59]

0.53 [0.26, 0.79]

Year

1986

2009

1980

2006

2009

2009

2010

2010

2011

2011


IV, Random, 95% CI

-4 -2 0 2 4

Favours fructose Favours controlFavors fructose Favors any CHO


(any CHO)

N

(fructose)


Overweight/obese



Subtotal

1986

2009

7

17

7

17

1.10 [-0.08, 2.28]

1.30 [0.67, 1.93]

1.26 [0.70, 1.81]



Normal-weight


Le et al. [59]


Le et al. [60] (N)





Subtotal

1980

2006

2009

2009

2010

2010

2011

2011

8

7

8

16

11

12

10

16

8

7

8

16

11

12

10

16

0.50 [-0.54, 1.54]

0.20 [-0.61, 1.01]

1.00 [-0.26, 2.26]

0.60 [-0.00, 1.20]

0.60 [0.07, 1.13]

0.30 [-0.01, 0.61]

0.20 [-0.98, 1.38]

-0.10 [-0.87, 0.67]

0.37 [0.15, 0.58]



Total 0.53 [0.26, 0.79]




(any CHO)

N

(fructose)


Overweight/obese



Subtotal

1986

2009

7

17

7

17

1.10 [-0.08, 2.28]

1.30 [0.67, 1.93]

1.26 [0.70, 1.81]



Normal-weight


Le et al. [59]


Le et al. [60] (N)





Subtotal

1980

2006

2009

2009

2010

2010

2011

2011

8

7

8

16

11

12

10

16

8

7

8

16

11

12

10

16

0.50 [-0.54, 1.54]

0.20 [-0.61, 1.01]

1.00 [-0.26, 2.26]

0.60 [-0.00, 1.20]

0.60 [0.07, 1.13]

0.30 [-0.01, 0.61]

0.20 [-0.98, 1.38]

-0.10 [-0.87, 0.67]

0.37 [0.15, 0.58]



Total 0.53 [0.26, 0.79]





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) ‘Ca

taly

tic

’ f

ructo

se &

card

iom

eta

bo

lic r

isk

(Br

J N

utr

, 2

01

2;1

08:4

18

-23

)

Lack of harm in SUBSTITUTION trials: >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%

-4 -3 -2 -1 0 1 2 3 4

Harm in ADDITION 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%

-4 -3 -2 -1 0 1 2 3 4

What about other fructose-containing

sugars?

“Substitution trials”= Energy from sugars substituted for

other sources of energy in the diet

“Addition trials”= Energy from sugars “added” to the diet

“Subtraction trials” = Energy from sugars “subtracted”

from the diet

3 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


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.

Adults

“Subtraction trials”

Reduction in energy from sugar reduces excess body fatness in

adults but not children: WHO commissioned systematic review and meta-analysis of 30 RCTs


Mattes et al. Obes Rev. 2011;12:346-65


Reduction in energy from SSBs does not affect weight across trials

but leads to less weight gain in overweight/obese subjects: A systematic review and meta-analysis of 8 RCTs (n=3281)

Malik et al. AJCN. 2013 Oct;98(4):1084-102.

Reduction in energy from SSBs may not reduce weight in children: A systematic review and meta-analysis of 5 RCTs (n=2772)

Children

Take away messages

Take away messages

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. Any threshold for the effect of sugars on body weight and cardiometabolic risk

is highly dependent on energy balance.

3. There are many pathways to overconsumption leading to weight gain and its

downstream consequences. Dietary patterns that bring these pathways

together have the greatest influence on weight gain and cardiometabolic risk

and represent the best opportunity for successful interventions.

4. Attention needs to remain focused on reducing overconsumption of all caloric

foods (including those high in added sugars!), promoting healthier dietary

patterns, and increasing physical activity.

Acknowledgements

sugars, obesity, and cardiometabolic...

Documents