Trials of diet and lifestyle modifications: Food fights and other battles
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Transcript of Trials of diet and lifestyle modifications: Food fights and other battles
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