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T h e n e w e n g l a n d j o u r n a l o f m ed i c i n e

n engl j med 355;19 www.nejm.org november 9, 20061992

Obesity in the united states has

reached epidemic proportions. Leading

research and medical societies advocate alow-fat, high-carbohydrate, energy-deficient dietto manage weight.1-4Despite these recommenda-

tions, diets high in fat and protein and low in car-

bohydrate remain popular, and several best-sellingbooks endorse this strategy for weight loss.5-9

The long-term safety of carbohydrate-restricted

diets remains controversial. Most such diets tendto encourage increased consumption of animalproducts and therefore often contain high amounts

of saturated fat and cholesterol. This may causeunfavorable changes in serum lipid levels and in-

crease the risk of coronary heart disease. Severalprofessional organizations have cautioned against

the use of low-carbohydrate diets.10-13

We devised a system to classify women whoparticipated in the Nurses Health Study according

to their relative levels of fat, protein, and carbohy-drate intake and created a simple summary score

designated the low-carbohydrate-diet score. Wethen examined prospectively the association be-

tween the low-carbohydrate-diet score and therisk of coronary heart disease in this cohort.

Methods

Study population

The Nurses Health Study was initiated in 1976,

when 121,700 female registered nurses 30 to 55years of age completed a mailed questionnaire.

Since 1976, information on disease status and life-style factors has been collected from this samecohort every 2 years. Diet was assessed by means

of a semiquantitative food-frequency questionnairein 1980, 1984, 1986, 1990, 1994, and 1998; 98,462

women completed the 1980 questionnaire.For this investigation we excluded all women

at baseline who left 10 or more food items blank

or had implausibly high (>3500 kcal) or low (

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Low-Carbohydrate-Diet Score and Coronary Heart Disease

n engl j med 355;19 www.nejm.org november 9, 2006 1993

in the next stratum received 9 points, and so on

down to women in the lowest stratum, who re-ceived 0 points. For carbohydrate, the order of

the strata was reversed; those with the lowest car-bohydrate intake received 10 points and those

with the highest carbohydrate intake received

0 points. We used the percentage of energy con-sumed instead of absolute intake to reduce bias

due to underreporting of food consumption andto represent dietary composition.

The points for each of the three macronutri-ents were then summed to create the overall diet

score, which ranged from 0 (the lowest fat andprotein intake and the highest carbohydrate in-take) to 30 (the highest protein and fat intake

and the lowest carbohydrate intake). Therefore,the higher the score, the more closely the partic-

ipants diet followed the pattern of a low-carbo-hydrate diet. Thus, the score was termed the low-

carbohydrate-diet score.We also created two additional low-carbohy-

drate-diet scores. One was calculated according

to the percentage of energy as carbohydrate, thepercentage of energy as animal protein, and the

percentage of energy as animal fat, and the otherwas calculated according to the percentage of

energy as carbohydrate, the percentage of energyas vegetable protein, and the percentage of en-ergy as vegetable fat (Table 1).

Measurement of Nondietary Factors

In 1976, women provided information regarding

parental history of myocardial infarction. Begin-ning in 1976, participants also provided informa-

tion every 2 years on the use of postmenopausal

hormones, smoking status, body weight, and oth-er covariates. They provided information on aspi-

rin use repeatedly throughout the follow-up. Thecorrelation coefficient between self-reported body

weight and measured weight was 0.96.18Physical

activity was assessed in 1980, 1982, 1986, 1988,1992, 1996, and 1998, and we calculated the cu-

mulative average number of hours per week spentin moderate or vigorous physical activity.19

Outcome

The outcome of this study was incident coronaryheart disease, including nonfatal myocardial in-farctions or fatal coronary events. Each partici-

pant contributed follow-up time from the dateof returning the 1980 questionnaire to the date

of the f irst end point (death or nonfatal myocar-dial infarction) or until the censoring date of

June 1, 2000.We requested permission to examine the med-

ical records of all participants who reported a di-

agnosis of coronary heart disease on one of thefollow-up questionnaires that were completed ev-

ery two years. A myocardial infarction was con-sidered to be confirmed if it met the World Health

Organization criteria of symptoms and eithertypical electrocardiographic changes or elevatedcardiac-enzyme levels.20 Infarctions that neces-

sitated a hospital admission and for which con-firmatory information was obtained by interview

or letter but for which no medical records were

available were designated as probable and wereincluded in the analysis.

Table 1.Criteria for Determining the Low-Carbohydrate-Diet Score.

PointsCarbohydrate

IntakeTotal Protein

IntakeTotal Fat

IntakeAnimal-Protein

IntakeAnimal-Fat

IntakeVegetable-

Protein IntakeVegetable-Fat

Intake

percentage of energy

0 >56.0

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Table2.Characteristics

oftheParticipantsin1990AccordingtotheLo

w-Carbohydrate-DietScores.*

Variable

IntakeofCarbohydrate,To

talProtein,

andTotalFat

IntakeofCarbohydrate,AnimalProtein,

andAnimal

Fat

IntakeofCarbohydrate

,VegetableProtein,

andVegetableFat

Decile1

Decile5

Decile10

Decile1

Decile5

Decile10

Decile1

Decile5

Decile10

Low-carbohydrate-dietscore

Median

5.0

14.0

26.0

4.5

13.3

27.0

8.0

14.3

21.8

Interquartilerange

3.76.3

13.514.2

24.527.0

3.05.5

13.013.8

26.028.0

6.09.0

14.014.5

21.023.0

No.ofparticipants

7787

8381

3693

8305

9761

2902

5200

808

0

7749

Ageyr

56.07.1

56.07.3

55.97.3

56.07.3

56.06.9

56.07.0

56.07.2

55.9

7.2

56.07.0

Body-massindex

24.64.4

25.64.6

26.75.5

24.54.6

25.74.9

26.35.4

25.45.0

25.7

4.5

25.55.3

Parentalhistoryofmyocardial

infarction%

(no.)

19(1480)

20(1676)

21(776)

19(1578)

20(1952)

22(638)

20(1040)

21(1697)

20(1550)

Useofpostmenopausalhormones

%

(no.)

26(2025)

27(2263)

22(813)

27(2242)

27(2636)

18(522)

20(1040)

27(2182)

28(2170)

PhysicalactivityM

ET

-hr/wk

2125

1923

1721

2125

1924

1622

1925

20

24

1921

Currentsmoker%

(n

o.)

17(1324)

16(1341)

26(960)

15(1246)

17(1659)

27(784)

24(1248)

16(1293)

20(1550)

Alcoholconsumption

g/day

4.08.5

5.510.1

4.37.2

3.16.6

5.69.9

4.98.4

3.99.0

5.0

8.9

6.39.5

Historyofhypertension

%

(no.)

14(1090)

13(1090)

15(554)

13(1080)

13(1269)

16(464)

15(780)

15(1212)

13(1007)

Historyofhypercholesterolemia

%(no.)

5(389)

5(419)

4(148)

5(415)

5(488)

4(116)

4(208)

5(404)

5(388)

Calorieskcal/day

1814528

1768501

1539490

1825527

1764504

1472491

1740523

1735

506

1775513

Glycemicindex

54.33.9

52.83.4

50.84.6

54.23.3

52.83.6

50.45.6

53.44.8

52.8

4.0

52.63.2

Glycemicload

14548

11737

7328

14347

11638

6527

13149

118

42

10737

Cerealfiberg

/day

6.33.9

5.73.4

3.42.3

6.74.1

5.63.6

2.92.3

4.53.2

5.6

4.0

5.63.2

Fruitsandvegetables

servings/day

5.82.6

5.11.8

4.21.8

5.82.7

5.12.0

4.32.2

5.22.9

5.2

1.8

4.71.8

Coffeecups/day

1.61.8

1.91.8

2.31.8

1.61.8

1.92.0

2.32.1

1.71.4

1.8

1.8

2.11.8

The New England Journal of Medicine

Downloaded from nejm.org on September 26, 2012. For personal use only. No other uses without permission.

Copyright 2006 Massachusetts Medical Society. All rights reserved.

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Redmeatservings/d

ay

0.80.9

1.20.9

2.41.2

0.80.9

1.21.0

2.71.6

1.40.7

1.2

0.9

1.20.9

Wholegrainsserving

s/day

1.61.6

1.50.9

1.01.2

1.81.7

1.50.9

0.81.1

1.01.1

1.4

0.8

1.71.6

Refinedgrainsservin

gs/day

2.31.6

2.11.7

1.51.2

2.41.7

2.11.8

1.32.1

1.71.1

2.0

1.6

2.21.6

Nutsservings/day

0.10.2

0.10.2

0.20.3

0.20.3

0.10.2

0.10.2

0.10.1

0.1

0.1

0.40.5

Poultryservings/day

0.20.2

0.30.2

0.40.2

0.20.2

0.30.2

0.40.2

0.30.2

0.3

0.2

0.30.2

Fishservings/day

0.20.2

0.30.2

0.30.3

0.20.2

0.30.2

0.30.3

0.30.3

0.3

0.2

0.30.2

Magnesiummg/day

29478

30478

28471

30079

30275

28168

28482

303

83

30270

Multivitaminuse%

(no.)

32(2492)

33(2766)

14(517)

32(2658)

32(3124)

8(232)

23(1196)

32(2586)

29(2247)

Macronutrientintake

%ofenergy

Protein

15.92.3

19.03.4

22.83.4

16.02.5

19.02.7

24.23.8

18.23.7

19.1

3.2

18.73.2

Animalprotein

10.53.1

13.93.4

18.33.8

10.42.5

13.92.7

20.33.8

14.03.7

14.1

4.0

13.03.2

Vegetableprotein

5.31.6

5.10.8

4.51.1

5.61.6

5.10.9

4.00.8

4.21.1

5.0

0.8

5.60.8

Carbohydrate

58.87.0

49.95.9

36.86.1

57.96.6

49.76.3

34.76.3

55.68.0

50.9

7.3

45.47.1

Totalfat

26.95.4

31.45.1

39.85.3

28.15.7

31.55.4

39.65.8

27.15.8

30.4

5.7

35.85.5

Animalfat

13.33.9

17.04.2

24.45.7

13.04.1

17.14.5

27.45.3

17.55.3

17.2

4.9

16.94.8

Vegetablefat

13.63.9

14.34.2

15.35.3

15.24.9

14.34.5

12.24.3

9.62.7

13.1

3.2

18.94.8

Polyunsaturatedfat

5.31.6

5.91.7

7.01.9

5.71.6

5.91.8

6.31.8

4.41.1

5.6

1.6

7.41.6

Transfat

1.40.8

1.50.8

1.70.8

1.50.8

1.50.9

1.60.5

1.20.5

1.4

0.8

1.70.8

Saturatedfat

9.02.3

10.62.5

13.72.7

9.12.5

10.72.7

14.33.0

10.12.7

10.5

2.4

11.42.4

*PlusminusvaluesaremeansSD.

Thebody-massindexis

theweightinkilogramsdividedbythesquare

oftheheightinmeters.

Dataformetabolicequivalents(MET)perweekarefrom1992.

Glucosewasusedasth

ereferenceforcalculationsofglycemicindexandglycemicload.

Redmeatisthecompo

sitescoreofbeef,pork,andlambasamaind

ishormixeddish;hamburgers;hotdogs;bacon;andprocessedmeats.




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Deaths were identified from state vital rec-

ords and the National Death Index or reported bythe participants next of kin or the U.S. Postal

Service.21Fatal coronary heart disease was con-firmed by an examination of autopsy or hospitalrecords, by a listing of coronary heart disease as

the cause of death on the death certif icate, andby the availability of evidence of previous coronary

heart disease. Those deaths in which coronaryheart disease was the underlying cause on the

death certificate but for which no medical records

were available were designated as deaths frompresumed coronary disease.

Statistical analysis

We divided women into 10 categories (deciles) ac-

cording to their low-carbohydrate-diet score. Torepresent long-term intake and reduce measure-

ment error, we calculated the cumulative averagelow-carbohydrate-diet score based on the infor-

Table 3.Relative Risk of Coronary Heart Disease in Women According to Low-Carbohydrate-Diet Score.*

Variable Decile 1 Decile 2 Decile 3 Decile 4 Decile 5

Intake of carbohydrate, total protein, and total fat

No. of cases 209 231 237 220 193

No. of person-yr 159,884 154,779 159,889 172,548 139,412Low-carbohydrate-diet score

Median 5.0 8.5 10.5 12.3 14.0

Range 07.0 7.29.6 9.711.4 11.513.0 13.214.6

Age- and smoking-adjusted relative risk(95% CI)

1.0 1.01 (0.841.22) 1.03 (0.861.25) 0.94 (0.781.14) 0.96 (0.791.17)

Multivariate relative risk (95% CI) 1.0 1.07 (0.881.29) 1.07 (0.891.29) 0.96 (0.801.17) 0.98 (0.811.20)

Intake of carbohydrate, animal protein,and animal fat

No. of cases 203 236 225 193 207

No. of person-yr 159,405 154,190 160,608 151,959 163,035

Low-carbohydrate-diet score

Median 4.5 7.8 10.0 11.6 13.3

Range 06.3 6.48.8 9.010.7 10.812.4 12.514.0


1.0 1.10 (0.911.32) 1.06 (0.881.28) 0.98 (0.801.19) 1.03 (0.851.25)


Intake of carbohydrate, vegetable protein,and vegetable fat

No. of cases 188 207 201 208 214

No. of person-yr 159,133 168,416 150,037 155,131 147,974

Low-carbohydrate-diet score

Median 8.0 10.5 12.0 13.0 14.3

Range 09.5 9.611.0 11.212.6 12.713.8 14.014.8


1.0 0.98 (0.801.19) 0.86 (0.701.05) 0.82 (0.671.0) 0.89 (0.731.09)


* Multivariate relative risks were adjusted for age (in 5-year categories), body-mass index (

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mation from the 1980, 1984, 1986, 1990, 1994,

and 1998 questionnaires.22For example, the low-carbohydrate-diet score from the 1980 question-naire was related to the incidence of coronary

heart disease between 1980 and 1984, and the low-carbohydrate-diet score from the average of the

1980 and 1984 questionnaires was related to theincidence of coronary heart disease between 1984

and 1986. Incidence rates for coronary heart dis-ease were calculated by dividing cases by the per-son-years of follow-up for each decile of the low-

carbohydrate-diet score. Relative risks of coronaryheart disease were calculated by dividing the rate

of occurrence of coronary heart disease in eachdecile by the rate in the first (lowest) decile. We

used Cox proportional-hazards models23to ad-

just for potentially confounding variables. Becauselow-carbohydrate diets may decrease subsequentenergy intake,24we did not control for total energy

intake in multivariate models. However, furtheradjustment for caloric intake was performed in a

secondary analysis. We also examined the asso-ciation between each macronutrient and the risk

of coronary heart disease in multivariate nutrient-density models.22All P values are two-sided.

Res ult s

The cumulative average low-carbohydrate-dietscore ranged from a median of 5.0 in the 1st decile

Table 3.(Continued.)

Decile 6 Decile 7 Decile 8 Decile 9 Decile 10P Value

for Trend

189 219 186 163 147

159,210 172,499 146,394 159,179 160,248

15.4 17.0 19.0 22.0 26.0

14.716.2 16.318.0 18.220.2 20.323.3 23.430.0

0.92 (0.751.12) 1.02 (0.851.24) 1.08 (0.891.32) 0.97 (0.791.20) 1.11 (0.891.38) 0.54

0.90 (0.741.10) 1.00 (0.821.21) 1.02 (0.831.24) 0.90 (0.731.11) 0.94 (0.761.18) 0.19

250 193 180 172 135

171,442 149,805 145,890 168,039 159,668

15.0 17.0 19.3 22.5 27.0

14.216.0 16.218.0 18.220.8 21.024.5 24.630.0

1.18 (0.981.43) 1.11 (0.911.35) 1.12 (0.911.37) 1.15 (0.941.42) 1.16 (0.921.46) 0.09

1.13 (0.941.36) 1.04 (0.851.27) 1.02 (0.831.26) 1.01 (0.811.24) 0.94 (0.741.19) 0.52

175 258 188 217 138

151,136 201,153 136,944 168,976 145,143

15.3 16.5 17.8 19.0 21.8

15.015.8 16.017.0 17.218.2 18.320.0 20.230.0

0.70 (0.570.87) 0.81 (0.670.98) 0.79 (0.640.97) 0.77 (0.630.94) 0.60 (0.480.75)

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to a median of 26.0 in the 10th decile (Table 2).The mean daily carbohydrate intake ranged from

234.4 g in the 1st decile to 116.7 g in the 10th dec-ile. At the midpoint of follow-up (1990), women

who had a higher score were more likely to smokeand had a higher body-mass index, a lower dietary

glycemic load, a lower caloric intake, and a high-er intake of saturated fat. On average, body-mass

Table 4.Relative Risk of Coronary Heart Disease in Women According to Consumption of Macronutrients.*

Variable Decile 1 Decile 2 Decile 3 Decile 4 Decile 5

relative risk (95% CI)

Carbohydrate

Age- and smoking-adjusted 1.0 1.07 (0.861.33) 1.19 (0.961.48) 1.06 (0.851.33) 1.06 (0.851.33)Multivariate 1.0 1.07 (0.861.34) 1.21 (0.971.51) 1.09 (0.871.37) 1.09 (0.861.38)

Glycemic load

Age- and smoking-adjusted 1.0 0.96 (0.761.21) 0.88 (0.691.11) 0.93 (0.731.17) 0.80 (0.621.02)

Multivariate 1.0 1.02 (0.801.30) 0.99 (0.751.30) 1.07 (0.791.45) 0.93 (0.661.30)

Total protein


Multivariate 1.0 0.94 (0.771.14) 0.97 (0.801.19) 0.89 (0.731.09) 1.09 (0.901.32)

Animal protein


Multivariate 1.0 1.08 (0.891.32) 1.15 (0.951.40) 1.07 (0.871.31) 1.08 (0.881.32)

Vegetable proteinAge- and smoking-adjusted 1.0 0.88 (0.701.10) 0.89 (0.711.11) 0.99 (0.801.23) 0.87 (0.691.08)

Multivariate 1.0 0.93 (0.741.16) 0.98 (0.771.23) 1.11 (0.881.41) 1.02 (0.801.30)

Total fat


Multivariate** 1.0 1.18 (0.991.42) 1.02 (0.841.23) 1.04 (0.861.26) 0.99 (0.811.20)

Animal fat


Multivariate 1.0 1.07 (0.891.29) 1.13 (0.941.37) 0.95 (0.781.16) 0.82 (0.671.01)

Vegetable fat


Multivariate 1.0 0.87 (0.701.09) 1.10 (0.891.37) 1.01 (0.811.27) 0.94 (0.741.18)

* Multivariate relative risks were adjusted for age (in 5-year categories), body-mass index (

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index increased by approximately 2.5 units frombaseline to the end of follow-up, regardless of the

low-carbohydrate-diet score.Because the Nurses Health Study did not rou-

tinely collect data on blood lipid levels, the effectof a low-carbohydrate diet on lipids could not be

assessed for the entire study cohort. However, asubgroup of women from the study (466 women)had blood drawn in 1990 for determinations of

lipid levels. In this subgroup, the low-carbohy-drate-diet score was not associated with the total

cholesterol level or with the levels of high-den-sity lipoprotein (HDL) cholesterol or low-density

lipoprotein (LDL) cholesterol after adjustment forage, smoking status, and other covariates. The low-carbohydrate-diet score was inversely associated

with the triglyceride level (126.5 mg per deciliterin the lowest quintile and 99.3 mg per deciliter

in the highest quintile of the low-carbohydrate-diet score, P for trend = 0.05).

During 20 years of follow-up (1,584,042 per-son-years), we documented 1994 cases of coro-

nary heart disease. In age-adjusted analyses, therelative risk comparing women in the 10th decile

with those in the 1st decile of the low-carbohy-drate-diet score was 1.29 (95% confidence interval[CI], 1.04 to 1.60). After further adjustment for

smoking status, the relative risk of coronary heartdisease was 1.11 (95% CI, 0.89 to 1.38) compar-

ing women in the same deciles of the low-carbo-hydrate-diet score (P for trend = 0.54) (Table 3).

After controlling for potential confounders, therelative risk was 0.94 (95% CI, 0.76 to 1.18; P fortrend = 0.19). Further adjustment for total calo-

ries did not appreciably alter the results (relativerisk, 0.96; 95% CI, 0.77 to 1.20; P for trend = 0.27).

Table 4.(Continued.)

Decile 6 Decile 7 Decile 8 Decile 9 Decile 10P Value

for Trend

relative risk (95% CI)

1.21 (0.971.50) 1.10 (0.891.37) 1.18 (0.951.47) 1.21 (0.981.50) 1.17 (0.941.45) 0.091.26 (1.001.58) 1.15 (0.911.46) 1.24 (0.981.57) 1.28 (1.011.62) 1.22 (0.951.56) 0.06

0.76 (0.600.98) 0.98 (0.781.24) 0.87 (0.681.10) 1.08 (0.861.37) 1.13 (0.901.43) 0.10

0.95 (0.661.37) 1.27 (0.871.86) 1.20 (0.791.82) 1.64 (1.042.57) 1.90 (1.153.15) 0.003

0.85 (0.701.04) 0.99 (0.821.20) 0.95 (0.781.15) 0.85 (0.691.03) 1.14 (0.941.38) 0.23

0.89 (0.721.09) 1.02 (0.831.24) 0.96 (0.781.17) 0.82 (0.671.02) 1.06 (0.861.30) 0.97

1.17 (0.961.42) 1.05 (0.861.28) 1.07 (0.871.31) 1.10 (0.901.35) 1.22 (0.991.50) 0.10

1.16 (0.951.42) 1.04 (0.851.28) 1.06 (0.861.30) 1.05 (0.851.30) 1.13 (0.911.41) 0.65

0.78 (0.630.98) 0.87 (0.701.08) 0.84 (0.671.04) 0.76 (0.610.95) 0.80 (0.631.00) 0.009

0.94 (0.731.21) 1.06 (0.821.36) 1.05 (0.811.35) 0.97 (0.741.26) 1.08 (0.821.43) 0.59

1.13 (0.931.37) 1.18 (0.971.43) 1.15 (0.941.40) 1.26 (1.041.54) 1.18 (0.951.46) 0.05

1.07 (0.881.30) 1.10 (0.881.30) 1.03 (0.841.26) 1.11 (0.911.36) 0.99 (0.791.23) 0.86

1.21 (1.001.47) 1.22 (1.011.49) 1.24 (1.011.52) 1.30 (1.061.61) 1.36 (1.081.72) 0.003

1.06 (0.861.29) 1.03 (0.841.27) 1.01 (0.821.26) 1.02 (0.811.28) 0.98 (0.751.28) 0.66

1.02 (0.821.27) 0.91 (0.731.14) 0.89 (0.711.11) 0.91 (0.721.14) 0.86 (0.691.09) 0.09

0.99 (0.781.25) 0.87 (0.681.11) 0.82 (0.641.06) 0.82 (0.631.06) 0.75 (0.570.98) 0.006




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When body-mass index was removed from the

multivariate model, the results did not changesignificantly.

In stratified analyses, there was no evidencethat the relationship between the low-carbohy-

drate-diet score and coronary heart disease was

modified as a result of body-mass index, level ofphysical activity, smoking status, or the presence

or absence of diabetes, hypertension, or hypercho-lesterolemia. Specific data on blood lipid levels

were not available for most of the cohort. As aresult, it was not feasible to adjust or stratif y our

analysis for this factor.We also created a second low-carbohydrate-

diet score according to the percentages of energy

from carbohydrate, animal protein, and animal fat(Table 1). The multivariate relative risk of coro-

nary heart disease was 0.94 (95% CI, 0.74 to 1.19)for the comparison of the 10th with the 1st dec-

ile (P for trend = 0.52) (Table 3). We also createda third low-carbohydrate-diet score according tothe percentages of energy from carbohydrate, veg-

etable protein, and vegetable fat (Table 1). For thecomparison of the 10th with the 1st decile, the

multivariate relative risk of coronary heart diseasewas 0.70 (95% CI, 0.56 to 0.88; P for trend = 0.002)

(Table 3).We examined the association between coro-

nary heart disease and each macronutrient sepa-

rately (Table 4). Total carbohydrate intake wasassociated with a moderately increased risk of

coronary heart disease (P for trend for the com-

parison of the 10th decile with the 1st dec-ile = 0.06). For the comparison of the 10th withthe 1st decile, there was a significant direct as-sociation between dietary glycemic load and coro-

nary heart disease (relative risk, 1.90; 95% CI,1.15 to 3.15; P for trend = 0.003). The overall di-

etary glycemic index had a direct associationwith the risk of coronary heart disease (relative

risk comparing extreme deciles, 1.19; 95% CI,0.91 to 1.55; P for trend = 0.04). There was a sig-

nificant inverse association between vegetable-fat consumption and the risk of coronary heartdisease (relative risk comparing extreme deciles,

0.75; 95% CI, 0.57 to 0.98; P for trend = 0.006).Total fat, animal fat, total protein, animal protein,

and vegetable protein were not significantly as-sociated with the risk of coronary heart disease

according to multivariate analyses.

Discussion

We found that after taking into account con-founding variables (especially smoking status),

a low-carbohydrate diet was not associated witha risk of coronary heart disease in this large pro-

spective cohort of women. In fact, when vegeta-ble sources of fat and protein were chosen, thelow-carbohydrate-diet score was associated with

a moderately lower risk of coronary heart diseasethan when animal sources were chosen.

The 20-year follow-up incorporating updateddietary data and the large number of women in

the study provided adequate power for this study.We reduced the measurement error in assessing

long-term diet in this analysis with the use of re-peated measures of diet during the follow-up. Al-though we adjusted for many known risk factors,

we cannot completely exclude the possibilit y of

residual or unmeasured confounding, because ofthe observational nature of the study.

Few people in our cohort followed the strict

version of the Atkins low-carbohydrate-diet pro-gram long-term.7However, the amount of car-bohydrate in the highest category of carbohydrate

intake in our cohort (27% of dietas protein), our results did not change signif i-

cantly.The low-carbohydrate-diet score did not have

a significant long-term effect on weight. On aver-age, body-mass index increased by approximate-

ly 2.5 units from baseline to the end of follow-up, regardless of the score. Since the participantsin the Nurses Health Study did not necessarily

subscribe to a low-carbohydrate diet for the spe-cific purpose of weight loss, this result is not un-

expected. However, it does indicate that the effectsof the low-carbohydrate-diet score on outcomes

in this analysis were not mediated by weight loss.Any assessment of the association between the

low-carbohydrate-diet score and a risk of coro-

nary heart disease must take each macronutrientinto consideration. Different types of fat appear

to have different effects on the risk of coronaryheart disease. In epidemiologic studies, saturat-




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ed22,26,27and trans22,28-30fats have been associated

with an increased risk of coronary heart disease,and polyunsaturated and monounsaturated fats

with decreased risk.22Total dietary fat, however,has not been associated with a risk of coronary

heart disease. In the Womens Health Initiative,

a low-fat dietary pattern was not associated witha reduced risk of coronary heart disease during

an 8-year follow-up.31Therefore, the increase intotal fat that is common among women who fol-

low low-carbohydrate diets would not be expectedto increase the risk of coronary heart disease.32

In low-carbohydrate diets, dietary protein usu-ally increases at the expense of carbohydrate. Inour previous analyses, we found that a moder-

ately high protein intake was significantly as-sociated with a slightly reduced risk of coronary

heart disease.33In this study, however, only veg-etable protein was associated with a significantly

reduced risk in age-adjusted analyses, and thisassociation became nonsignificant in multivari-ate analyses.

Another possible explanation for the null as-sociation between a low-carbohydrate-diet score

and the risk of coronary heart disease relates tothe amount and quality of carbohydrate present in

the diet.34A low-carbohydrate diet tends to havea lower dietary glycemic index and glycemic loadthan a high-carbohydrate diet. In a 10-year pro-

spective analysis of the Nurses Health Study, Liuet al. found a relative risk of coronary heart dis-

ease of 1.98 (95% CI, 1.41 to 2.77) for the com-

parison between the fifth and the first quintileof dietary glycemic load.17In our investigation, wefound that the direct association between glyce-mic load and coronary heart disease was much

stronger than the association between carbohy-drate and coronary heart disease, probably because

glycemic load reflects both the quantity and qual-ity of carbohydrates.

In a meta-analysis of five randomized trialscomparing a low-carbohydrate diet with a low-fat

diet for at least 6 months, the low-carbohydratediet was found to have a beneficial effect on HDLcholesterol and triglyceride levels but an adverse

effect on total cholesterol and LDL cholesterollevels.25However, none of the trials have a suffi-

ciently large sample size or a sufficiently long

duration of follow-up to be used to study the out-comes of coronary heart disease. In our study, data

on lipid levels were available for only a small sub-group of participants. In this group, the low-car-

bohydrate-diet score was not associated with

total cholesterol, HDL cholesterol, or LDL choles-terol levels but was inversely associated with the

triglyceride level. Therefore, it is not clear wheth-er these findings are applicable to any low-carbo-

hydrate diet that has an adverse effect on serumlipid levels.

Proponents of low-carbohydrate diets assertthat ketogenesis (the production of ketone bodies)is an important component of the overall effects

of such diets.7We were not able to measure keto-genesis in this investigation. Our investigation also

did not address other possible adverse consequenc-es of a low-carbohydrate diet in terms of a decline

in renal function, osteoporosis, a decrease in mi-cronutrient and fiber intake, and the risk of ma-lignant conditions. We have observed previously

in a subgroup of the Nurses Health Study thatdietary protein was not associated with a decline in

renal function in women with normal renal func-tion but may accelerate such a decline in women

who have mild renal insufficiency.35Therefore, thelong-term effects of high protein intake on renalfunction should be investigated further, especially

among people with compromised renal function,such as those with diabetes or renal disease.

In conclusion, diets lower in carbohydrate and

higher in protein and fat were not associated withan increased risk of coronary heart disease in thiscohort of women. When vegetable sources of fatand protein were chosen, these diets were related

to a lower risk of coronary heart disease.Supported by grants (CA87969, HL34594, HL60712, and

DK58845) from the National Institutes of Health. Dr. Hus re-search is partly supported by the American Heart AssociationEstablished Investigator Award.

Dr. Liu reports having received grant support from GeneralMills for a study on magnesium. Dr. Hu reports having receivedgrant support from the California Walnut Commission for astudy on alpha-linolenic acid. No other potential conflict of in-terest relevant to this article was reported.

We thank the women in the Nurses Health Study for their

participation and cooperation, and Dr. Meir Stampfer for helpfulcomments.

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