substitution of dietary protein for carbohydrate: associations of disease and mortality in a...

Substitution of Dietary Protein for Carbohydrate: Associations of

Disease and Mortality in a Prospective Study of

Postmenopausal Women

LE Kelemen, LH Kushi, DR Jacobs Jr., JR Cerhan

Mayo Clinic College of Medicine, Rochester, MN

University of Minnesota, Minneapolis, MN

Kaiser Permanente, Oakland, CA

Background

• Popular high protein (HP) diets extol benefits for weight loss

– Often do not discriminate among protein types

• Effect of protein & protein type on long term health outcomes not widely studied

Objectives

Using multivariable nutrient density models:1) To estimate the effect of an isoenergetic

substitution of total protein for total carbohydrate with cancer incidence and mortality from cancer, CHD and all causes in the IWHS

2) To estimate the effect of an isoenergetic substitution of one type of protein for another type of protein with these outcomes

• In 1986: 99,826 Iowa women aged 55-69 yrs (now 71-86)

• Identified from randomly selected driver’s licenses• Mailed questionnaire

– diet (FFQ)– self-reported lifestyle, medical & reproductive history

• 41,836 (41.9%) enrolled

Study Population

Dietary Assessment• Semi-quantitative Harvard FFQ• Validation study, 1988, 44 Iowa women

– average of five 24-hour recalls over 2 months:

» r = 0.16 ( protein)» r = 0.45 (carbohydrate)» r = 0.43-0.62 (fats)

• Reproducibility (2.5 yrs)» r = 0.59 (protein)» r = 0.53 (carbohydrate)» r = 0.47-0.57 (fats)

Follow-Up

• Questionnaires mailed in 1987, 1989, 1992 and 1997

• Incident cancers identified by linkage to Iowa SEER cancer registry

• Deceased non-respondents & cause of death identified by linkage to National Death Index

• 15 years follow-up

Excluded– Premenopausal women (n=569)– Prior history of cancer (n=3,881)– Known heart disease (n=5,116)– Known diabetes (n=2,675)– Diet

30 blanks on FFQ• total energy (kcal/d) 600 or 5,000 (n=3,096)

• 29, 017 eligible women

Eligibility Criteria

Data Analysis• Dietary exposures

– Macronutrients expressed as nutrient densities (i.e. % of energy from protein, carbohydrate and fats)

– Micronutrient covariates were energy-adjusted (Willett & Stampfer 1986)

– Categorized into quintiles

• RR (95% CI) estimated using Cox proportional hazards with lowest intake category as referent; age as time metric

• Multivariable-adjusted nutrient density models (Willett 2nd ed 1998 p 295; Hu AJE 1999; Willett AJCN 1997)– Estimate associations from an increase in the % energy from

protein intake– By forcing total energy and other intake (i.e., dietary fats) to be

constant, and by excluding carbohydrate from the model, modeling the effects of an increase in protein intake, by definition, statistically results in a decrease in carbohydrate intake

– Thus, the effect estimates of protein assume a substitution interpretation

– The % of energy from protein that is “substituted” for carbohydrate is the difference between the median intake in the highest and lowest quintiles

– Models also adjusted for other risk factors

Data Analysis

Covariates• Known/suspected confounders & risk factors:

– Total energy– Fats (saturated, poly-, mono- & trans) (all quintiles & expressed as %

of energy)– Total fiber, dietary cholesterol, dietary methionine (all quintiles &

energy-adjusted)– Alcohol (≤14 vs > 14 g/d)– Smoking (never, former, current)– Activity level (active vs not active)– BMI (5 levels)– History of HTN– PM hormone use– Education (≤ high school vs > high school)– Family history of cancer– Multivitamin use– Vitamin E supplement use

Results

• 475,755 person-years

• Outcomes:– 4,843 incident cancers– 739 CHD deaths– 1,676 cancer deaths– 3,978 deaths from all causes

Table 1 Distribution of baseline characteristics by quintiles of total protein among 29,017 Iowa women, 1986

Quintiles of total protein (% of total energy)

Subject characteristics 1(14.1)

2(16.3)

3(17.8)

4(19.4)

5(22.0)

Age, y 76 76 76 76 75

Education > high school, % 34 39 42 44 44

Physical activity, active % 23 26 29 29 34

Current smokers, % 19 14 14 14 14

Alcohol >14 g/d, % 13 9 8 6 4

Body mass index, kg/m2 25 26 26 26 27

Vitamin E supplement use, % 14 15 14 14 16

Table 1 cont.

Nutrient intakes 1(14.1)

2(16.3)

3(17.8)

4(19.4)

5(22.0)

Carbohydrates, % energy 53.7 50.8 48.9 46.8 43.9

Total fat, % energy 33.1 33.9 34.2 34.7 34.5

Saturated fat, % energy 10.9 11.5 11.7 12.1 12.3

Polyunsat. fat, % energy 6.3 6.1 5.9 5.7 5.5

Monounsat. fat, % energy 12.7 12.9 13.0 13.2 12.9

trans fat, % of energy 1.9 1.7 1.6 1.6 1.4

Cholesterol, mg/d 205 239 261 272 297

Total fiber, g/d 19.6 20.4 20.3 19.4 18.2

Methionine, g/d 0.27 0.45 0.55 0.65 0.79


Table 1 cont.

Food intakes, servings / 1,000 kcals

1(14.1)

2(16.3)

3(17.8)

4(19.4)

5(22.0)

Processed & red meat A 0.52 0.62 0.67 0.72 0.73

Chicken & poultry 0.07 0.08 0.09 0.11 0.19

Fish & seafood 0.06 0.08 0.09 0.11 0.16

Dairy products B 1.00 1.13 1.24 1.34 1.45

Eggs 0.09 0.12 0.14 0.14 0.16

Nuts, tofu and legumes 0.12 0.13 0.14 0.14 0.13

Whole grains C 0.56 0.67 0.69 0.68 0.68

Refined grains D 2.86 2.52 2.26 1.99 1.49

Sweets and desserts 0.79 0.63 0.52 0.43 0.29

Fruits and vegetables 2.44 2.67 2.72 2.81 3.01


A composite of beef, pork, processed meatB composite of milk, cream, ice-cream, yogurt, cheeseC composite of dark bread, brown rice, oatmeal, whole grain cereal, bran, wheat germ & other grains (bulgar, kasha, couscous)D composite of rice, pasta, potatoes, refined cold breakfast cereal, muffins, snack foods, sweetened sodas, pizza, chocolate, cakes, cookies

Table 2 RR (95% CI) for CHD mortality by quintiles of total protein intake (% energy) substituted for isoenergetic amount of carbohydrate, IWHS 1986 to 2001

Quintiles of intake P

1 2 3 4 5 (95% CI) trend

Total protein

Median (% energy) 14.1 16.3 17.8 19.4 22.0

Multivariable RR* 1 0.72 0.56 0.71 0.84 (0.39, 1.79) 0.62

Animal protein

Median (% energy) 8.9 11.3 12.9 14.7 17.5

Multivariable RR 1 0.99 0.88 0.81 0.88 (0.42, 1.86) 0.29

Vegetable protein

Median (% energy) 3.7 4.3 4.8 5.3 6.1


*adjusted for dietary fats, total energy plus other covariates

Table 3 RR (95% CI) for cancer incidence by quintiles of total protein intake (% energy) substituted for isoenergetic amount of carbohydrate, IWHS


1 2 3 4 5 (95% CI) trend

Total protein

Median (% energy) 14.1 16.3 17.8 19.4 22.0


Animal protein

Median (% energy) 8.9 11.3 12.9 14.7 17.5


Vegetable protein

Median (% energy) 3.7 4.3 4.8 5.3 6.1



Table 4 RR (95% CI) for cancer mortality by quintiles of total protein intake (% energy) substituted for isoenergetic amount of carbohydrate, IWHS


1 2 3 4 5 (95% CI) trend

Total protein

Median (% energy) 14.1 16.3 17.8 19.4 22.0


Animal protein

Median (% energy) 8.9 11.3 12.9 14.7 17.5


Vegetable protein

Median (% energy) 3.7 4.3 4.8 5.3 6.1



Table 5 RR (95% CI) for all cause mortality by quintiles of total protein intake (% energy) substituted for isoenergetic amount of carbohydrate, IWHS


1 2 3 4 5 (95% CI) trend

Total protein

Median (% energy) 14.1 16.3 17.8 19.4 22.0


Animal protein

Median (% energy) 8.9 11.3 12.9 14.7 17.5


Vegetable protein

Median (% energy) 3.7 4.3 4.8 5.3 6.1



Table 6 RR (95% CI) of vegetable protein intake (% of energy) substituted for isoenergetic amount of animal protein for different outcomes

Quintiles of vegetable protein intake P

1 2 3 4 5 (95% CI) trend

Median (% energy) 3.7 4.3 4.8 5.3 6.1

CHD mortality


Cancer incidence


Cancer mortality


All cause mortality


*adjusted for carbohydrate, dietary fats, total energy, plus other covariates

Table 7 Multivariable RR* for protein foods substituted for an isoenergetic amount of carbohydrate foods (svgs/1000 kcals) for different outcomes

Quintiles of intake P Δ Svg/1,000 kcals Q5:Q1Svgs/1,000 kcals 1 2 3 4 5 (95% CI) trend

CHD mortality

Legumes 1 0.89 0.91 0.81 0.83 (0.65, 1.07) 0.08 0.5

Dairy 1 1.13 1.26 1.26 1.41 (1.07, 1.87) 0.02 2.1

Red meats 1 1.10 1.09 1.29 1.44 (1.06, 1.94) 0.02 0.9

Cancer mortality

Legumes 1 1.17 1.14 1.23 1.23 (1.04, 1.46) 0.02 0.5

Dairy 1 0.98 1.08 0.87 0.97 (0.80, 1.17) 0.43 2.1

Red meats 1 0.93 0.87 0.92 1.04 (0.85, 1.27) 0.52 0.9

All cause mortality

Legumes 1 1.03 0.99 1.08 1.10 (0.99, 1.23) 0.09 0.5

Dairy 1 1.03 1.05 0.98 1.10 (0.97, 1.24) 0.36 2.1

Red meats 1 0.97 0.98 1.05 1.16 (1.02, 1.32) 0.02 0.9*adjusted for dietary fats, total energy, other covariates & quintiles of svgs/1000kcals: fruits & veg, eggs, poultry, fish, legumes, dairy, red meats

Summary

• Similar ↓ in risk of CHD mortality when vegetable protein substituted for carbohydrate or animal protein– suggests animal protein & carbohydrate may have similar potentially

adverse effects on CHD mortality

• Animal protein not associated with any outcome– ↑ risk of CHD mortality for red/processed meat servings (RR=1.44)

and dairy servings (RR=1.41) when substituted for carbohydrate foods

– Modest risk of red/processed meat servings with all cause mortality (RR=1.16)

• Modest risk of legume servings with cancer mortality (RR=1.23) but not with cancer incidence

• No associations with cancer incidence

Strengths & Limitations

• Strengths– Prospective – Large # of events– Adjust for large # of covariates

• Limitations– Baseline diet only– No blood samples– Food substitution analyses: measuring non-

protein components?• Red meat & CHD – consistent with others’ findings

(Snowdon 1984, Hu 1999, Liu 2004)

Conclusions

• Dietary protein from animal and vegetable sources appear to be differentially associated with mortality from CHD & all causes when substituted in the diet

• Long-term adherence to popular HP diets, without discrimination toward protein source, may have potentially adverse health consequences

Appendix - Protein Food Groupings• Legumes/nuts/tofu

– composite of tofu, dried beans, nuts and peanut butter • Dairy

– composite of milk, cream, ice-cream, yogurt and cheese • Eggs• Red meats

– composite of beef, pork and processed meat • Poultry

– composite of chicken and turkey • Fish

– composite of fresh fish, canned fish and seafood • Fruits & Vegetables

– Including juices, excluding potatoes• Carbohydrate foods = referent

– composite of refined carbohydrates (rice, pasta, potatoes, refined cold breakfast cereal, muffins, snack foods, sweetened sodas, pizza, chocolate, cakes, cookies), and

– whole grain carbohydrates (dark bread, brown rice, oatmeal, whole grain breakfast cereal, bran, wheat germ and other grains such as bulgar, kasha and couscous)

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