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

1
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

2
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

3
Objectives

• Using multivariable nutrient density models
• 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
• To estimate the effect of an isoenergetic
  substitution of one type of protein for another
  type of protein with these outcomes

4
Study Population

• In 1986 99,826 Iowa women aged 55-69 yrs (now
  71-86)
• Identified from randomly selected drivers
  licenses
• Mailed questionnaire
• diet (FFQ)
• self-reported lifestyle, medical reproductive
  history
• 41,836 (41.9) enrolled

5
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)

6
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

7
Eligibility Criteria

• Excluded
• Premenopausal women (n569)
• Prior history of cancer (n3,881)
• Known heart disease (n5,116)
• Known diabetes (n2,675)
• Diet
• ? 30 blanks on FFQ
• total energy (kcal/d) ? 600 or ? 5,000 (n3,096)
• 29, 017 eligible women

8
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

9
Data Analysis

• 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

10
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 gt 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 gt high school)
• Family history of cancer
• Multivitamin use
• Vitamin E supplement use

11
Results

• 475,755 person-years
• Outcomes
• 4,843 incident cancers
• 739 CHD deaths
• 1,676 cancer deaths
• 3,978 deaths from all causes

12
Table 1 Distribution of baseline characteristics
by quintiles of total protein among 29,017 Iowa
women, 1986
Quintiles of total protein ( of total energy) Quintiles of total protein ( of total energy) Quintiles of total protein ( of total energy) Quintiles of total protein ( of total energy) 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 gt high school, 34 39 42 44 44
Physical activity, active 23 26 29 29 34
Current smokers, 19 14 14 14 14
Alcohol gt14 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
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Table 1 cont.
Quintiles of total protein ( of total energy)
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
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Table 1 cont.
Quintiles of total protein ( of total energy)
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 meat B
composite of milk, cream, ice-cream, yogurt,
cheese C 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
15
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 Quintiles of intake Quintiles of intake Quintiles of intake 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
Multivariable RR 1 0.88 0.86 0.75 0.70 (0.49, 0.99) 0.02
adjusted for dietary fats, total energy plus
other covariates
16
Table 3 RR (95 CI) for cancer incidence by
quintiles of total protein intake ( energy)
substituted for isoenergetic amount of
carbohydrate, IWHS
Quintiles of intake Quintiles of intake Quintiles of intake Quintiles of intake 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 0.99 1.01 1.08 1.24 (0.92, 1.67) 0.18
Animal protein
Median ( energy) 8.9 11.3 12.9 14.7 17.5
Multivariable RR 1 0.96 0.92 0.99 1.02 (0.76, 1.37) 0.95
Vegetable protein
Median ( energy) 3.7 4.3 4.8 5.3 6.1
Multivariable RR 1 0.94 0.96 0.95 0.99 (0.87, 1.14) 0.99
adjusted for dietary fats, total energy plus
other covariates
17
Table 4 RR (95 CI) for cancer mortality by
quintiles of total protein intake ( energy)
substituted for isoenergetic amount of
carbohydrate, IWHS
Quintiles of intake Quintiles of intake Quintiles of intake Quintiles of intake 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 1.00 1.02 1.03 1.07 (0.64, 1.79) 0.81
Animal protein
Median ( energy) 8.9 11.3 12.9 14.7 17.5
Multivariable RR 1 0.94 0.80 0.76 0.77 (0.47, 1.27) 0.31
Vegetable protein
Median ( energy) 3.7 4.3 4.8 5.3 6.1
Multivariable RR 1 0.97 1.04 1.07 1.04 (0.83, 1.32) 0.43
adjusted for dietary fats, total energy plus
other covariates
18
Table 5 RR (95 CI) for all cause mortality by
quintiles of total protein intake ( energy)
substituted for isoenergetic amount of
carbohydrate, IWHS
Quintiles of intake Quintiles of intake Quintiles of intake Quintiles of intake 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 0.95 0.81 0.84 0.99 (0.71, 1.38) 0.67
Animal protein
Median ( energy) 8.9 11.3 12.9 14.7 17.5
Multivariable RR 1 0.93 0.83 0.79 0.82 (0.59, 1.13) 0.24
Vegetable protein
Median ( energy) 3.7 4.3 4.8 5.3 6.1
Multivariable RR 1 0.90 0.95 0.93 0.95 (0.82, 1.10) 0.74
adjusted for dietary fats, total energy plus
other covariates
19
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 Quintiles of vegetable protein intake Quintiles of vegetable protein intake Quintiles of vegetable protein intake 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
Multivariable RR 1 0.86 0.83 0.74 0.70 (0.51, 0.98) 0.02
Cancer incidence
Multivariable RR 1 0.94 0.96 0.94 0.99 (0.87, 1.13) 0.92
Cancer mortality
Multivariable RR 1 1.00 1.09 1.13 1.11 (0.89, 1.38) 0.29
All cause mortality
Multivariable RR 1 0.93 0.98 0.98 0.99 (0.86, 1.14) 0.82
adjusted for carbohydrate, dietary fats, total
energy, plus other covariates
20
Table 7 Multivariable RR for protein foods
substituted for an isoenergetic amount of
carbohydrate foods (svgs/1000 kcals) for
different outcomes
Quintiles of intake Quintiles of intake Quintiles of intake Quintiles of intake Quintiles of intake P ? Svg/1,000 kcals Q5Q1
Svgs/1,000 kcals 1 2 3 4 5 (95 CI) trend ? Svg/1,000 kcals Q5Q1
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
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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 (RR1.44) and dairy servings (RR1.41)
  when substituted for carbohydrate foods
• Modest risk of red/processed meat servings with
  all cause mortality (RR1.16)
• Modest risk of legume servings with cancer
  mortality (RR1.23) but not with cancer incidence
• No associations with cancer incidence

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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)

23
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

24
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)