Trials of diet and lifestyle modification:

Food fights and other battles

Lawrence J. Appel, MD, MPH

Professor of Medicine, Epidemiology and International Health (Human Nutrition)

Johns Hopkins Medical Institutions

Sept 2, 2009

Outline• Context

– Research setting – Scientific rationale

• Trials– Completed– Ongoing

• Lessons, challenges, and battles

• Academic home– Welch Center for Prevention, Epidemiology and

Clinical Research

• Implementation setting– ProHealth Clinical Research Unit

Research Settings

• Off-campus, community-based, primary data collection unit

• Over 50 completed studies• ~ 15,000 sq ft of space

– metabolic kitchen– behavioral intervention suites– numerous offices, data collection rooms– laboratory: three -70 freezers

• ~ 30 interdisciplinary staff (nurses, dietitians, behavioral interventionists, data collectors)

Scientific Rationale• Blood pressure related cardiovascular and

kidney diseases are massive public health problems

• Diet is etiologically related to elevated blood pressure and its complications

• Lifestyle modification has tremendous but unrealized potential to prevent blood pressure-related CVD and CKD and reduce racial disparities

Magnitude of the BP Problem

• 62% of strokes and 49% of CHD events attributed to elevated BP*

• 26% of adults worldwide (971 million) have hypertension**

• Estimated lifetime risk of developing hypertension is 90%***

*WHO, World Health Report 2002: Reducing Risks, Promoting Healthy Life, **Kearney Lancet 2005;305:217, ***Vasan, JAMA 2002;287:1003.

Stroke Mortality by Level of Usual Systolic BP*

*Source: Prospective Studies Collaboration, Lancet, 2002: Meta-analysis of 61 prospective studies with 2.7m person-yrs, 11.9k deaths

Definition of Hypertension

Blood Pressure Classification (JNC VII)

Category Systolic BP Diastolic BP

Normal < 120 and < 80

Pre-hypertension 120-139 or 80–89

Hypertension

Stage 1

Stage 2

140–159

>160

or

or

90–99

>100

Distribution of BP Levels in US Adults, Ages 18 and Older (NHANESIII)

“Normal”

<120/80

PrehypertensionSBP 120-39 or DBP 80-89

HypertensionSBP > 140 orDBP > 90

Source: Wang, Hypertension, 2004

42% 27%

31%

Prevalence of High Blood Pressure by Age and Race/Ethnicity, Women, Age 18 and Older

* Extimate is based on sample size not meeting requirement of NHANES III design or relative standard error is greater than 30 percent.

100

30

20

10

0

Perc

en

t

40

Black (excludes Hispanic Blacks)

80

70

60

50

90White (excludes Hispanic Whites)

Mexican American

18-29

2.0*

1.0*

0.6*

30-39

11.3

6.2

4.6*

40-49

30.5

10.612.7

50-59

47.9

33.536.8

60-69

77.8

59.3

50.9

70-79

72.6

67.066.9

80 +

80.5*

71.0*

74.3

Source: Burt V, et al. Hypertension, 1995

Mean SBP and DBP by Age and Race/Ethnicity for Women, Age 18 Years and Older

150

140

130

120

110

100

90

80

70

mm

Hg

18-29 30-39 40-49 50-59 60-69 70-79 80+

Diastolic

Systolic

Source: Burt V, et al. Hypertension, 1995

SBP Rise with Age = ~0.6 mmHg per year

BlackWhite

Mexican-American

Age

Roles of Non-Pharmacologic (“Lifestyle”) Therapies

Normotensives - Reduce Blood Pressure

- Prevent Hypertension

- Prevent Age-Related Rise in BP

Hypertensives - Initial Therapy

- Adjunct to Drug Therapy

- Substitute for Medication

Effects of Population-Based BP Reduction (Shifting SBP Distribution Downward)

Effects of Population-Based BP Reduction (Shifting SBP Distribution Downward)

Stamler R. Hypertension1991;17:I-16–I-20.Stamler R. Hypertension1991;17:I-16–I-20.

Reduction in SBPmmHg

235

Reduction in SBPmmHg

235

% Reduction in Mortality % Reduction in Mortality

Reduction in BP

Reduction in BP

After Intervention

After Intervention

Before InterventionBefore Intervention

Stroke CHD Total

-6 -4 -3-8 -5 -4-14 -9 -7

Completed Trials

Types of Trials

Type of Trial Research Question Examples

Feeding Studies Effects of Diet Change on Blood Pressure and Other Risk Factors

DASH

DASH-Na

OmniHeart

Behavioral Intervention Studies

Feasibility and Effects of Lifestyle Change in Free-Living Individuals

TOHP1

TOHP2

TONE

PREMIER

Wt Loss Maintenance

Dietary

Approaches to

Stop

Hypertension

DASH Centers

BrighamHopkins

NHLBIDuke

Pennington

CHR

Objective

• To determine the effects on BP of modifying whole dietary patterns, while controlling known determinants of BP

Run-in and Intervention Periods

3 wks 8 weeksRun-in Intervention

ControlDiet

Control

F & V

Combination

Randomization

Baseline Characteristics

• Number of Participants 459• % Women 49%• % African-American 60%• Mean Age 45 yrs• Mean Blood Pressure 132/85 mmHg• % Hypertensive 29%• Mean Body Mass Index 28.7 kg/m2 (W)

27.7 kg/m2 (M)

The DASH Diet

Emphasizes:Fruits, Vegetables, Low-fat Dairy Foods

Includes:Whole Grains, Nuts, Poultry, Fish

Reduced in:Fats, Red Meat, Sweets, and Sugar-containing Beverages

The DASH diet

WEEKS

78

80

82

84

86122

124

126

128

130

132

134CONTROLF/VDASH Diet

B 1 2 3 4 5 6 7,8

DIA

STO

LIC

SY

STO

LIC

Weekly BP by Diet During Intervention Feeding

Appel, NEJM 1997;336:1117

Effect of DASH Diet by BP Status

-14

-12

-10

-8

-6

-4

-2

0

Ch

ang

e in

BP

.

Systolic BPDiastolic BP

Hypertensives Non-Hypertensives

* †

* *

*

* p< 0.05 (main effect)† p< 0.05 (BP status interaction)

The DASH diet: Can it be improved?

Objective

• Determine, in the setting of a healthy diet, the effects of partially replacing carbohydrate with:– protein (about half from plant sources) or– unsaturated fat (mostly monounsaturated fat)

on blood pressure, serum lipids, and estimated CHD risk

Participant Flow

Period 16 weeks

Period 26 weeks

Period 36 weeks

Randomization to 1 of 6

sequences

Washout Period2–4 wk

Washout Period2-4 wk

BP, Lipids:

Run-In6 days

Participants Ate Study Food

Screening/Baseline

Participants Ate Their Own Food

Macronutrient Goals, % kcal

CARB*

Carbohydrate 58

Protein 15

Fat 27

Monounsaturated 13

Polyunsaturated 8

Saturated 6

*Similar to DASH diet. All diets were healthy: cholesterol 150 mg/d, fiber 30 g/d, sodium 100 mmol/d, potassium 120 mmol/d, magnesium 500 mg/d, calcium 1,200 mg/d

Macronutrient Goals, % kcal

CARB* PROT

Carbohydrate 58 48

Protein 15 25

Fat 27 27

Monounsaturated 13 13

Polyunsaturated 8 8

Saturated 6 6

*Similar to DASH diet. All diets were healthy: cholesterol 150 mg/d, fiber 30 g/d, sodium 100 mmol/d, potassium 120 mmol/d, magnesium 500 mg/d, calcium 1,200 mg/d

Macronutrient Goals, % kcal

CARB* PROT UNSAT

Carbohydrate 58 48 48

Protein 15 25 15

Fat 27 27 37

Monounsaturated 13 13 21

Polyunsaturated 8 8 10

Saturated 6 6 6

*Similar to DASH diet. All diets were healthy: cholesterol 150 mg/d, fiber 30 g/d, sodium 100 mmol/d, potassium 120 mmol/d, magnesium 500 mg/d, calcium 1,200 mg/d

Systolic Blood Pressure

-20

-15

-10

-5

0

mm

Hg

CARB* PROT UNSAT CARB* PROT UNSAT

All (n = 164)Baseline mean = 131.2 mmHg

Hypertension (n = 32) Baseline mean = 146.5 mmHg

p = 0.002

-1.4

-1.3

p = 0.005

-20

-15

-10

-5

0

-2.9

p = 0.02

-3.5

p = 0.006

*CARB similar to DASH diet

Appel, JAMA 2005;294:2455

LDL Cholesterol

-25

-20

-15

-10

-5

0

mg

/dL

CARB* PROT UNSAT CARB* PROT UNSAT

All (n = 161)Baseline mean = 129.2 mg/dL

LDL ≥ 130 mg/dL (n = 75) Baseline mean = 156.7 mg/dL

p = 0.01

-3.3 +1.5

p = 0.24

-1.5

p = 0.22

-25

-20

-15

-10

-5

0

-2.1

p = 0.33

+1.7

p = 0.45

-3.9

p = 0.09

*CARB similar to DASH diet

Effects of Reducing (Substituting) Carbohydate on BP in Hypertensives

Partially Substituting Carbohydrate with:

Carb (% kcal)

Reduction

Net SBP

Net DBP

Soy Protein1 -3.7% -7.9 -5.3

Mixed Protein2 -10% -3.5 -2.4

Lean Red Meat3 -5.3% -5.2 +0.2

Monounsat Fat2 -10% -2.9 -1.9

1He, Ann Int Med, 2005; 2Appel, JAMA, 2005; 3Hodgson, AJCN, 2006

Salt Matters

Key Studies Supporting the Role of Sodium Reduction as a Means to Lower BP

Non-Hypertensives Study

Reduce BP DASH-Na

Prevent hypertension TOHP 2

Prevent age-related rise in BP INTERSALT

Prevent CVD events TOHP 3

Hypertensives

Initial therapy DASH-Na

Adjunct to drug therapy TONE

Substitute for medication TONE

Percent Reduction in Incident Hypertension over 36-48 Months from Weight Loss and Sodium Reduction Interventions in TOHP2

-80%

-60%

-40%

-20%

0%

Weight Loss

Sodium Reduction

Combined

6 Months

18 Months

End of Study

* *

*

**

* * *

* P <0.05

Control Diet

Randomization

Run-in:(11-14 days)

Intervention (Three 30-day periods, random order)

Intermediate Sodium

Higher Sodium

Lower Sodium

Higher Sodium

Intermediate Sodium

Lower Sodium

Study Design

Control Diet, N = 204

DASH Diet, N = 208N = 412

Effect of Sodium Level on Systolic Blood Pressure

120

125

130

135

SystolicBlood

Pressure Control Diet

DASH Diet

Higher Intermed Lower

Sodium Level (mmol/d)

- 2.1

- 1.3- 1.7

- 4.6- 6.7p<.0001

- 3.0P<.0001

Sacks, NEJM 2001;344:3 (143) (106) (65)

120

125

130

135

SystolicBlood

Pressure

Control Diet

DASH Diet

Higher Intermed Lower

Sodium Level

-2.2p=.02

-5.0p=.0003

-5.9p<0.0001

Effect of DASH Diet on Systolic Blood Pressure

Interactive Effects of Reduced Na and DASH Diet on Systolic BP

120

125

130

135

SystolicBlood

Pressure

Higher LowerSodium Level

Na Effect in Control Diet = - 6.7

DASH Effect - 5.7

Combined* Effects Actual = - 8.9 Predicted = - 12.4

* P < 0.001, Strict Additivity

Effects of Reduced Na on CVD Events:

Results from 3 Randomized Trials

INTERVENTION OUTCOME FU

TONE (2001) 639 Elderly

↓ Na21% ↓

CVD events2.3 yrs

Taiwan Veterans (2006) 1,981 Elderly

↓ Na /↑ K Salt

41%* ↓CVD

Mortality2.6 yrs

TOHP Follow-up [abs] 3,126 Prehypertensives

↓ Na30%* ↓

CVD events10-15 yrs

*p<0.05

Effects of Reduced Na Intake on CVD: Longterm Results from the Trials of Hypertension Prevention (Cook et al, BMJ, 2007)

Adj RR = 0.70

p=0.02

Opportunities to Reduce Racial

Disparities in BP

Effect of Na Reduction (Higher to Lower) in African-Americans and Non-African-Americans on Typical American Diet

-12

-10

-8

-6

-4

-2

0

Ch

ang

e in

BP

Systolic BP Diastolic BP

African-Americans Non-African-Americans

- 8.0†

P<.001

- 4.5†

P<.001 - 5.1

P<.001

- 2.2

P<.001

0 † P-interaction < 0.05

Effect of DASH Diet By Race

-8

-7

-6

-5

-4

-3

-2

-1

0

Ch

an

ge

in B

P

Systolic BPDiastolic BP

African-Americans Non-African-Americans

* †

* *

*

* p< 0.05 (main effect)† p< 0.05 (race interaction)

Older-aged individuals can

make and sustain lifestyle changes that control BP

-6

-5

-4

-3

-2

-1

0

Time (months) after Randomization

Cha

nge

in W

eigh

t (kg

)

No Weight Loss (n=294)

Weight Loss (n=291)

Mean Change in Weight (kg) by Randomized Group in Older-Aged Persons (TONE)

0 9 18 30

Whelton JAMA 1998;279:839.

-50

-40

-30

-20

-10

0

10

Time (months) after Randomization

Cha

nge

in U

rinar

y N

a

No Sodium Reduction (n=488)

Sodium Reduction (n=487)

Mean Change in Urinary Sodium Excretion (mmol/24hr) in Older-Aged Persons (TONE)

0 9 18 30

Whelton JAMA 1998;279:839.

What are the effects of comprehensive lifestyle modification on blood pressure and hypertension control?

Appel, JAMA 2003;289:2083

Design

ADVICE ONLY

EST

EST + DASH

Randomization

Primary Outcomes (6 months)

End of Intervention (18 months)= Data Visit

-7

-6

-5

-4

-3

-2

-1

0

Baseline 6 months 18 months

Advice EST EST+DASH

Change in Weight (kg) (Baseline Wt = 97 kg)

**

*p<0.001 vs Advice

Chan

ge in

Wt

(Kg)

-12

-10

-8

-6

-4

-2

0

Baseline 6 months 18 months

Advice EST EST+DASH

Change in Fitness* (Baseline = 130 beats/min)

**p<0.05 vs Advice

Chan

ge in

HR

(B

eats

/min

)

* Heart Rate (beats/min at Stage 2 of exercise test)

-50

-40

-30

-20

-10

0

Baseline 6 months 18 months

Advice EST EST+DASH

Change in Urine Na Excretion (Baseline=170

mmol/24 hr)

*

*

* p < 0.05 vs Advice

Chan

ge in

Uri

ne N

a (

mm

ol/2

4

hr)

0

2

4

6

8

10

Baseline 6 months 18 months

Advice EST EST+DASH

Fruit and Vegetable Intake (servings/day)

* p <.001 EST+ DASH vs Advice+ p <.001 EST + DASH vs EST

* +

Fru

it a

nd

Veg

(s

erv

/day)

0

2

4

6

8

10

12

Baseline 6 months 18 months

Advice EST EST+DASH

Saturated Fat Intake (% kcal)

** p <.05 vs Advice* p <.0001 vs Advice+ p <.0001 EST+DASH vs EST

*+All Ptcp 6

**

Sat

Fat

Inta

ke (

%kc

al)

0%

20%

40%

60%

80%

100%

Baseline 6 months 18 months

Advice EST EST+DASH

Hypertension Prevalence (Among Those with

Hypertension at Baseline)

+ p <.01 vs Advice% w

ith H

yp

ert

en

sion

+++

+

0.5

11

.52

2.5

Me

dia

n F

ram

ing

ham

Ris

k (%

)

Advice Only EST EST+DASH

Baseline 6 Months

10-Year Probability of CHD Event

RR = 0.89 (0.84-0.94), P <0.001

RR = 0.87 (0.82-0.92), P <0.001

2005 Dietary Guidelines for

Americans

JNC VII – Hypertension

Prevention and Treatment Guidelines

2006 American Heart

Association Guidelines

Ongoing Trials

Practice-Based Opportunities for Weight Reduction (POWER) Trial

Awarded in Response to RFA from NHLBI:

“to test the effectiveness of interventions delivered in routine clinical practices on achieving wt loss in obese patients with CVD risk factors”

Three funded trials Harvard U. Penn Hopkins

Design

Self-Directed (SD) – comparison group

Call-Center Directed (CCD)

In-Person Directed (IPD)

Randomization

Last visits: 24 – 36 m after randomization

= Data Collection Points, every 6 months during follow-up

Description of Groups

Randomized Groups

Self-Directed (SD)

Call-Center Directed (CCD)

In-Person Directed (IPD)

Counselor: None Healthways Coach

Hopkins Coach

Static Website: √

InteractiveWeb-site:

√ √

Sessions: Telephone Only Group MtgsIndividual Telephone

PCP Reinforcement

√ √

CCD and IPD Intervention Goals

Weight Goal Minimum 5% weight loss, individually tailored

Behaviors

Calories 1200 kcal/d if ≤ 170 lb;1500 kcal/d if > 170 lb and < 220 lb;1800 kcal/d if > 220 lb and < 270 lb;2200 kcal/d if > 270 lb

Diet DASH diet7-12 services of fruits/vegetables2-3 servings of low fat dairylow sodium≤ 25% of calories from fat

Exercise Build to ≥ 180 minutes/wk of moderate intensity physical activity in bouts ≥ 10 minutes in length

Intervention Website

Coach Physician

Patient

Novel Intervention Website

Links Patient, Lifestyle Coach, and PCP

Could be routinely implemented if effective

Applicable to other chronic conditions

• Two clinical centers– Brigham and Woman’s Hosptial– Hopkins

• Coordinating unit– Channing Laboratory

• Sponsor– NHLBI

Optimal Macronutrient Intake for Carbohydrate

• Design: 4 period, randomized, crossover feeding • Objective: compare the effects of four diets on insulin

resistance, blood pressure, and lipids

• Participants: 160 overweight or obese individuals with high normal blood pressure or stage 1 hypertension without diabetes

Glycemic Index (GI) High GI (>65) Low GI (<45)

High Carb(58% Kcal)

Low Carb(40% kcal)

Lessons and Battles (Food Fights)

Lesson 1

• Get the sequence right– test efficacy then effectiveness– in retrospect, DASH-Na was the most powerful

study design to test the sodium hypothesis, NOT a behavioral change study (TOHP2)

Lesson 2

• Behavioral intervention trials are challenging to conduct and interprete– recruit motivated individuals, who then must

be willing to accept ‘control condition’ – participants don’t appreciate the commitments

required of ‘active’ intervention (e.g. diet change, physical activity, attendance)

– high risk of both ‘drop in’, ‘drop out’ and diminished effect size

Lesson 3

– Subadditivity of interventions is commonplace• implementation is incomplete in setting of

multi-factorial behavioral interventions• even under optimal conditions of high

adherence (feeding studies), effects have been subadditive

Lesson 4

– ‘Comparison’ groups in recent trials have made some behavioral changes that diminish net effect size, e.g. reduced weight and sodium in control group of PREMIER

Obstacle 1: Design

• By what process does one construct a dietary pattern?

– what are the key characteristics of the dietary pattern? nutrients or foods?

– what is the dose? • What is the control condition?

Obstacle 2: Logistics

• Usual challenges of multicenter clinical trials– recruitment, data collection, coordination across

centers• Additional challenges

– feeding protocol: purchase, preparation and distribution of food per protocol and according to hygienic standards

– behavioral interventions: assembly of cohorts– coordination of recruitment and data collection around

feeding or cohort schedules

Battle 1: Funding

• Feeding studies and lifestyle intervention trials are expensive (really expensive)

• Government (NIH) only logical funding source

• Pre-approval process at NIH– a major hurdle– more stringent over time

Costs of Lifestyle Intervention Trials

Sample

Size

Duration of Intervention

Total Costs

Per Participant

Costs

POWER 415 2 yr $5.9 m $14.2k

Costs of Feeding Studies

Sample

Size

Duration of Feeding

Total Costs

Per Participant

Costs

DASH 459 11wk $7.8 m $17k

DASH-Sodium

412 14 wk $11.8 m $29k

Omni Heart

160 19 wk $6.2 m $39k

Omni Carb

160 21 wk $10.3 m $64k

Costs of Mass Mailing in Feeding Studies

DASH DASH-Sodium OmniHeart

# Brochures Sent

115,000 265,000 393,000

# Enrolled from Mass Mailing

90 69 72

Yield/ 10k Brochures

7.8 2.6 1.8

Mailing Costs Per Enrolled

$486 $1,459 $2,074

Total Mailing Costs

$43,700 $100,700 $149,340

Pre-Approval Process

• If direct costs <$500k in each project year– No pre-approval

• If direct costs >$500k in any year but < $1.5m in all project years– Pre-approval by NHLBI branch director

• If direct costs > $1.5m in any one year– Pre-approval by NHLBI Director– Note: pre-approval requests for > $1.5m only

accepted twice each year

Battle 2: Vested Interests

• Advocacy Group – Physicians Committee for Responsible

Medicine (PCRM) concerned about inclusion of ‘dairy products’ as part of the DASH Diet

• Commercial Interests– Salt Institute (Trade Association) and

Chamber of Commerce (Business Federation) tenaciously promote salt

Battle 3: Interpretation and Policy

• Relatively few lifestyle trials have clinical outcomes, especially the general population– Multiple Risk Factor Intervention Trial (MRFIT)– Dietary Modification Trial of the Women’s Health

Initiative (WHI)

• Preventative guidelines inevitably rely on:– trials with well-accepted surrogate outcomes (BP,

LDL-C)– observational studies

Reduced Salt

“A”

Lower Blood Pressure

“A”

Fewer ASCVD Events

“B”

Categories of Evidence Linking Reduced Salt Intake to Fewer ASCVD Events

Categories of Evidence: A=Extensive Trial, B=Limited Trial, C=Observational Studies, D=Consensus of Experts

MI, CHD Death, or Revascularization(all participants)

Stroke

Time, y

HR, 0.97(95% CI, 0.90-1.06)

Comparison

Intervention

Time, y

HR,1.02(95% CI, 0.90-1.15)

Comparison

Intervention

Effects of WHI Dietary Modification Intervention on Total CVD and Stroke

Comparison of Lipids, Blood Pressure, and Framingham Risk Score Effects of WHI Diet and OMNI-Heart* Diets

*OMNI-Heart = Optimal Macronutrient Intake Trial to Prevent Heart DiseaseSource: Appel LJ, et al. JAMA 2005; 294:2455-64

OMNI-HeartWHI Carb Protein Unsat Fat(yr 3)

Total Chol (mg/dl) -3.3 -12.4 -19.9 -15.4

LDL-C -3.6 -11.6 -14.2 -13.1

HDL-C -0.4 -1.4 -2.6 -0.3

Triglycerides 0 0.1 -16.4 -9.3

SBP (mmHg) -0.2 -8.2 -9.5 -9.3

DBP (mmHg) -0.3 -4.1 -5.2 -4.8

Framingham Estimated 10-Yr Risk 3-4% 16% 21% 20%

Summary

• Feeding studies are powerful research tools that test diet-risk factor relationships

• Lifestyle intervention trials provide extremely useful information about ability of individuals to make and sustain lifestyle changes in the context of their usual environment

• Substantial obstacles impede the successful funding and conduct of these studies

Final Lesson• Always end with a good cartoon