Optimizing Macronutrient Composition for Health

Walter C. Willett, MD, DrPHDepartment of Nutrition

Harvard School of Public Health

May 12, 2009

Sponsored by the University of Arizona College of Medicine at the Arizona

Health Sciences Center

Walter Willett has nothing to disclose and no conflicts of interest. Dr. Willett will not be discussing the off-label or investigational use of any drugs, products or devices.

10-Year Coronary Incidence Per 10,000 Men

Keys, 1980

Incidence

0

1000

2000

3000

0 5 10 15 20 25% Diet Calories from Saturated Fat

DalmatiaVelika Krsna

Zrenjanin

BelgradeRome railroad

MontegiorgioCrevalcore

Corfu

Crete

Slavonia

Zutphen

west Finland

east Finland

Ushibuka

Tanushimaru

y=77+78xr=0.73

9.006

(Keys 1980)

Carroll, 1975

TaiwanJapan

Ceylon

El SalvadorThailand

Panama

PhilippinesMexico

ColumbiaSpain

Greece

Poland

Puerto Rico

ChileVenezuela

Hong Kong

RomaniaYugoslavia

CzechoslovakiaItaly

Portugal

Bulgaria

Australia

NorwayFrance

FinlandHungary

BelgiumSwitzerland

SwedenGermanyAustria

CanadaUKNetherlands

USA Ireland

New ZealandDenmark

0.001

0

5

10

15

20

25

0 20 40 60 80 100 120 140 160Animal Fat Intake (g/day)

Bre

ast C

ance

r Dea

ths

/ 100

,000

pop

Animal Fat and Breast Cancer Mortality

21.004

To reduce your fat intake:

Eat more fruits, vegetables, and their juices. Most are naturally low in fat…and high in vitamins and minerals.

Here are some other ways to reduce fat in your food.

TRY INSTEAD OF

Butter-flavored granules Butter or margarine Nonfat yogurt Regular yogurt Nonfat salad dressings Regular salad dressings Angel food cake Devil’s food cake Fat-free cookies and crackers High-fat cookies and crackers

1: Use Nonfat Products

9.071

21.031

21.038

0.248

(Howard et al. 2006)9.152

Breast Cancer Incidence in WHI

P=0.09

(Prentice et al. 2006)0.246

HR, 0.91 (95% CI, 0.83-1.01)

9.010

Omni Heart Study: Effect on Blood Pressure

(Appel et al. 2005)

OverallP-Value .002 .005 .90

9.191

Change (%) in Estimated 10-year Risk of Coronary Heart Disease Using Framingham Score

(Omni Heart Study)

Protein Unsaturated Fat

MenChange from carbohydrate

-5.6% -3.9%

WomenChange from carbohydrate

-11.1% -12.9%

(Appel et al. 2005)9.192

-0.15

-0.1

-0.05

0

0.05

0.1

0.15

0.2

Carbohydrates

ButterShortening

Margarine (stick)

Palm Oil

Chocolate Fat

Average US Dietary Fat

Coconut Fat

Margarine (Tub)

Palm Kernel Fat

Mayonnaise

Olive Oil

Soybean Oil

Rapeseed Oil

(Mensink RP, et al, 2003)

9.140

Total:HD

L Cholesterol

Blood lipids

Blood pressure

Thrombotic tendency

Insulin resistance

Oxidation

Homocysteine

Inflammation/endothelial dysfunction

Ventricular irritability & arrhythmia

Diet CHD

9.105R

Nurses’ Health Study (n=121,700)

Health Professionals Follow-up Study (n=52,000)

Nurses’ Health Study II (n=116,000)

Investigators: Frank Speizer, Bernie Rosner, Meir Stampfer, Graham Colditz, David Hunter, JoAnn Manson, Sue Hankinson, Eric Rimm, Edward Giovannucci, Alberto Ascherio, Gary Curhan, Charlie Fuchs, Fran Grodstein, Michelle Holmes, Frank Hu

1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000

DietOcsSmokingWeight/HtMed. Hist.

Diet Diet DietBlood

Diet Diet

1986 1988 1990 1992 1994 1996 1998 2000

Diet Diet DietBlood

Diet

1989 1991 1993 1995 1997 1999

Diet Diet DietBlood

0.198R

Nails

Nails

Percent of Energy from Fatand Plasma Triglyceride Level

020

406080

100120

140160

20% 20.1 - 25% 25.1 - 30% 30.1 - 35% 35.1 - 40% > 40%

NHS (n=185)HPFS (n=269)

% of Energy from Fat by FFQ

Mean TG

Level

20.091

100

80

60

40

20

0

-20

-40

1%E 2%E 3%E 4%E 5%E

Trans

Sat

Mono

Poly

% C

hang

e in

CH

D

(Hu et al. 1997)9.131

1

0.7

0.880.8

0.710.92 0.91

0.63 0.73 0.71

1.05

0.870.71

0.360.320.81

0.66 0.55 0.630.31

0

1.2

Q5

(hig

hest

)

Q4

Q3

Q2

Q1

(low

est)

Q5 (highest)

Q4

Q3

Q1&Q2

Quintiles of poly

Quintiles of trans fat

Mul

tivar

iate

RR

of C

HD

(Hu et al, 1997)

(lowest)

9.049

“Intake of total fat per se, independent of the relative content of different types of fatty acids, is not associated with high blood cholesterol levels and coronary heart disease”.

Diet and Health, 1989, page 7

9.030

0.6

0.8

1

1.2

1.4

Q1 Q2 Q3 Q4 Q5

Saturated FatMonoPolyTrans

Multivariate RRs of type 2 diabetes according to quintiles of Multivariate RRs of type 2 diabetes according to quintiles of specific types of dietary fat (mutually adjusted)specific types of dietary fat (mutually adjusted)

(Salmeron et al, 1999)

Quintiles of Fat Intake

Mul

tivar

iate

RR

25.004

% of Energy from Fat

Rel

ativ

e R

isk

0.133(Hunter et al. 1996)

0.0

0.5

1.0

1.5

<20 (

n=84)

<25 (

n=278

)<3

0 (n=8

24)

<35 (

n=117

1)<4

0 (n=1

173)

<45 (

n=802

)45

+ (n=4

95)

Fat & Postmenopausal Breast Cancer in NHS, 1980-2000 (3537 cases)

0

0.5

1

1.5

2

<=20

20.1-25

25.1-3030.1-35

35.1-4040.1-45

45.1-50>50

P, trend test 0.11

RR

of B

reas

t Can

cer

Cumulative Average Fat Intake (%E)

(Kim et al. 2006)0.255

Bray and Popkin prediction

26.063

Low-Fat Weight Loss Trials

-10

-5

0

5

10

0 6 12 21

Length of Follow-up (months)

Wei

ght L

oss D

iffer

ence

(kg)

NDH (1968)(35 vs 30% E)Boyd (1990) (37 vs 21% E)Jeffery (1995) (33 vs 26% E) Black (1994) (40 vs 21% E)Sheppard (1991) (38 vs 20% E)Kasim (1993) (36 vs 17% E)Simon (1997) (34 vs 18% E)Knopp (1997) (27 vs 22% E)McManus (2001) (35 vs 20% E) Bray and Popkin(10% E) (1998)

(Dansinger et al. 2005)

29.167

Protein Fat Carb

-5

-4.5

-4-3.5

-3

-2.5

-2

-1.5-1

-0.50

Cha

nge

in b

ody

wei

ght f

rom

bas

elin

e to

2 y

ears

, kg

High

Low oraverage

High-average:-0.6 (-1.6,0.4)

(P=0.22)

High-low:0.04 (-0.9,1.0)

(P=0.94)

Highest vs. lowest0.6 (-0.8,1.9)

(P=0.42)

PoundsLost: Primary Trial Outcome, 2 yearsBody Weight Change: All randomized participants

26.099

α-linolenic acid (α-LNA, 18:3)

EPA (20:5)

DHA (22:6)

N-3

anti-inflammatory

linoleic acid (LA, 18:2)

arachidonic acid (20:4)

thromboxanes, prostaglandins leukotrienes

Human eicosanoid synthesis

Δ-6-desaturase, elongase, Δ-5-desaturase

cyclooxygenase lipoxygenase

N-6

pro-inflammatory9.146 (Pischon et al. 2003)

Blood lipids

Blood pressure

Thrombotic tendency

Insulin resistance

Oxidation

Homocysteine

Inflammation/endothelial dysfunction

Ventricular irritability & arrhythmia

Diet CHD

9.105R

Keys

Serum chol = 1.35 (2 S - P) + 1.5 C0.5

Hegsted

Serum chol = 2.16 S – 1.65 P + 0.176 C

9.008

Total cholesterol = 1.51 (carb sat) – 0.12 (carb mono) – 0.60 (carb poly)

LDL-C = 1.28 (carb sat) – 0.24 (carb mono) – 0.55 (carb poly)

HDL-C = 0.47 (carb sat) + 0.34 (carb mono) + 0.28 (carb poly)

Triglycerides = -2.22 (carb sat) – 1.99 (carb mono) – 2.47 (carb poly)

All equations predict change expected as a result of 1% daily dietary energy intake as carbohydrate replaced by a particular fatty acid. Changes in lipids are in mg/dl.

(Mensink & Katan, 1992)9.075

sTN

F-R

2 (p

g/m

L)

Omega 3-fatty acid intake (quartile)

Omega 6-fatty acid intake (Quartile)

Association between omega-3 and omega-6 fatty acid intake and inflammation (HPFS+NHS2, n=859)*

*adjusted for age, gender, smoking status, physical activity, alcohol consumption, NSAID, BMI, energy intake, intake of protein, saturated fats, monounsaturated fats, and cholesterol; n=859

Pischon et al, Circulation 2003; 108: 155

1400

1500

1600

1700

1800

1900

1 2 3 4

12

34

p=0.002 for interaction

9.144

Trial of LA (N-6) on Inflammatory Factors

High LA (N-6) Low LA (N-6)

Percent of Energy 10.5% E 3.8% E

N-6/N-3 10:1 4:1

CRP (ng/L) 0.56 (± 0.15) 0.60 (± 0.21)

IL-6 (ng/L) 0.96 (± 0.33) 0.93 (± 0.30)

Platelet aggregation 85 (± 2.51) 81 (± 1.63)

(Liou YA, J Nutrition 2006)9.194

The Effect of Dietary Intervention with 5-week Periods of SFA or PUFA Diet in 17 Subjects ± SD

PUFA Diet SFA DietBody weight (kg) 80.8 ± 3.6 81.2 ± 3.7

BMI (kg/m2) 29.6 ± 1.6 29.7 ± 1.6

Total cholesterol (mmol/l) 5.0 ± 1.2 5.5 ± 1.4*

HDL-Cholesterol (mmol/l) 1.1 ± 0.27 1.1 ± 0.32

LDL-Cholesterol (mmol/l) 3.1 ± 1.1 3.6 ± 1.2**

Insulin sensitivity (μmol • 1 • mU-1 • kg-1 • min-1 ) 0.64 ± 0.43 0.51 ± 0.35****p = 0.001 **p = 0.002 ***p = 0.02

(Summers et al. 2002)

25.040

-50

-40

-30

-20

-10

0

10

0 2 4 6 8 10 12 14

Turpienen

9.043R

Low-fat diets High-polyunsaturated-fat-diets

MRC low fat

DartMRC Soy Oil

DaytonLeren

% o

f CH

D D

iffer

ence

-3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -13 -14 -15

% Change in Serum Cholesterol

(Sacks, 1994)

Prospective Studies of PUFA & CHD(Summarized in Nutritional Epidemiology, 1998)

• A significant inverse association was seen in 5 of 13 studies (Shekelle 1981; McGee 1984; Goldbourt 1993; Dolecek 1992; Hu 1997)

• In no study was a positive association observed

9.149

Nurses’ Health StudyDietary Fats and Risk of CHD

-80 -60 -40 -20 0 20 40 60 80

Sat -->Carbo (5%E)

Mono -->Carbo (5%E)

Poly --> Carbo (5%E)

Sat--> Mono (5%E)

Sat--> Poly (5%E)

Sat-->Unsat (5%E)

Trans--> Mono (2%E)

Trans --> Poly (2%E)

Trans --> Unsat (2%E)

Change in CHD Risk (%)

Hu et al, 19979.052

CHD Mortality

9.195(Jakobsen et al. 2009)

CHD Mortality

(Jakobsen et al. 2009)9.196

Ratio of ALA to LA & Risk of Fatal CHD in NHS (Hu, F. et al. AJCN 1999)

0

0.5

1

1.5

1 2 3 4 5

P, trend = 0.40Rel

ativ

e R

isk

Quintiles9.147

Dwyer & Hetzel, 1980

Mortality per 103

Coronary Heart Disease Mortality

100

200

300

400

500

600

700

1950

1954

1958

1962

1966

1970

1974

1978Fe

mal

eM

ale

United States United Kingdom Australia

9.112

Consumption of Animal and Vegetable Fat (g/day)

Dwyer & Hetzel, 1980

10

20

30

40

50

1935 1950 1954 1958 1962 1966 1970 1974

80

90

100

110

120

130

United States United Kingdom Australia

Veg

etab

le F

atA

nim

al F

at

9.113

Conclusions

• Both N-3 & N-6 fatty acids are essential• Ratio of N-6 to N-3 is not helpful• Many diets are more deficient in N-3 than N-6• Reducing N-6 to “improve” the ratio is likely to

increase the risk of CHD & diabetes• The upper limit for N-6 is not clear, but up to

roughly 10% of total energy intake appears to be increasingly beneficial

9.148

0

0.5

1

1.5

Women ( 591cases )Wolk et al. 1999

Men ( 734 cases )Rimm et al. 1996

RRof

CHD

Cereal Fiber, Energy- Adjusted, g/day

0

0.5

1

1.5

2.2 3.1 4.93.8 7.7 2.2 3.7 5.0 6.8 9.7

8.064

Blood Glucose

Insulin

Easily Digested Carbohydrate

-

Blood Glucose

Insulin

Slowly Digested Carbohydrate

0

0 1 2 3 4 5 0 1 2 3 4 5 Time (hr) Time (hr)

25.027

Relative Risk of Type 2 Diabetes by Different Levels of Cereal Fiber and Glycemic Load

2.5 2.32.05

2.171.8 1.62

1.511.28 1

0

1

2

3

High Medium Low

High

Medium

LowRelativeRisk

>165 165-143 <143Glycemic Load

>5.8 g/day

2.5 -5.8 g/day

<2.5 g/day

(Salmeron et al,1997)

(ref)

WOMEN

9.038

Cereal Fiber

1.501.85

1.061.001.39 1.41

1.00 1.11

0.00.51.01.52.02.5

<1/mo 1-4/mo 2-6/wk >=1/dSugar-sweetened soft drink consumption

Rel

ativ

e R

isk

multivariate adjusted multivariate + BMI

P<0.001 for trend

Regular Soft Drinks and Type 2 Diabetes, NHS2

(Schulze et al. 2004 JAMA)25.080

Correlation between baseline insulin resistance and increase in postprandial glucose, insulin, and triacylglycerol after increasing

dietary carbohydrate from 40-60% of energy

(n = 10 postmenopausal women)

Variables r P

Glucose 0.68 0.06

Insulin 0.82 < 0.02Plasma triacylglycerol 0.77 < 0.05

(Jeppesen et al. 1997)9.079R

Liu et al., 2000

Glycemic Load

9.072

Body Mass Index (kg/M2)

Rel

ativ

e R

isk

1.16

2 2

0.94 1.19

1.81

1 1.1 1.42

0

0.5

1

1.5

2

2.5

<23 23-29 >29

Tertile 1 (lowest)Tertile 2

Tertile 3 (highest)

Relative Risk of Coronary Heart Disease

Optimal macronutrients: Considerations

• Whole grains: CHO: fiber = about 6:1• for 30 gm of fiber/day, 180 gm CHO =

720 kcal• For 2500 kcal/day this is about 30% E• Fruits/vegetables add 10 to 15%

carbohydrate, or 40 to 45% E from CHO• Add 35 to 45% E from fat and 15 to 20% E

from protein

9.193

Lowfat products whenever possible; calcium supplements are and effective substitute for preventing fractures

Importance is well-documented; greens and dark orange vegetables should be included. Even more frequent servings may be desirable

Whole-grain, minimally processed products should be emphasized

Ignores critical differences in types of fat. Monos appear desirable

Misleading as 2-3 servings of meat/day is probably unhealthy

Support for generous intake is well documented

21.002

21.090

Healthy Eating Pyramid

Healthy Eating Pyramid

21.092

21.055

21.056