Comprehensive Approaches to Intervention
George A. Bray, MD, MACE
Pennington Biomedical Research Center
Louisiana State University
Baton Rouge, Louisiana
Key Points
• Weight loss is beneficial
• Several strategies will produce weight loss
– Lifestyle changes
– Diet
– Exercise
– Pharmacotherapy
• Summary
2
BMI Has Biggest Effect on Diabetes
Men
Women
6
6
5
5
4
4
3
3
2
2
1
1
0
<21 22 23 24 25 26 27 28 29 30
0
<21 22 23 24 25 26 27 28 29 30
BMI (kg/m2)
BMI (kg/m2)
Type 2 diabetes
Cholelithiasis
BMI, body mass index.
Willett WC et al. N Engl J Med. 1999;341(6):427–434.
Hypertension
Coronary heart disease
3
Small Weight Loss Reduces Risk of
Diabetes in the DPP
Weight Change in DPP (kg)
Placebo
Reduces Risk of
Diabetes by 58%
Lifestyle
0
6
12
18
24
30
36
42
48
Months in Study
DPP, Diabetes Prevention Program.
Knowler WC et al. N Engl J Med. 2002;346(6):393–403.
4
How Much Weight Loss Is Needed to
Prevent Type 2 Diabetes?
Incidence Rate
per 100 Person-Years
20
15
10
5
0
-10
-5
0
+5
Change in Weight From Baseline (kg)
Redrawn from: Hamman RF et al. Diabetes Care. 2006;29(9):2102–2107.
5
Key Points
• Weight loss is beneficial
• Several strategies will produce weight loss
– Lifestyle changes
– Diet
– Exercise
– Pharmacotherapy
• Summary
6
Components of Behavior Therapy for Obesity
Selfmonitoring
Problem
solving
Cognitive
restructuring
Contingency
management
Social
support
Stimulus
control
Stress
management
Wadden TA, Foster GD. Med Clin North Am. 2000:84(2):441–461.
7
Weight Change From Baseline (%)
4-Year Weight Loss in the Look AHEAD Trial
DSE
ILI
Year
Repeated measures adjusted for clinic and baseline level. P value for average effect across all visits: P < 0.0001.
DSE, diabetes support and education; ILI , intensive lifestyle intervention.
8
Look AHEAD Research Group, Wing RR. Arch Intern Med. 2010;170(17):1566–1575.
Lifestyle Intervention Was Clinically Effective in
All Subsets of an Ethnically and Demographically
Diverse Population
Reduction (%) in Initial Weight
in ILI Participants
0.0
African
American
Hispanic
Other/
Mixed
2.0
4.0
NonHispanic
White
Male
Female
6.0
8.0
10.0
12.0
Wadden TA et al. Obesity (Silver Spring). 2009;17(4):713–722.
9
Correlates of Weight Loss: Look AHEAD
Rank Order of Importance
1. Self-reported physical activity
2. Diet and physical activity counseling sessions attended
3. Consumption of meal replacements
• At 1 year, ILI participants lost more weight if:
– Attended more treatment sessions
– Exercised more
– Consumed more meal replacement products
10
Key Points
• Weight loss is beneficial
• Several strategies will produce weight loss
– Lifestyle changes
– Diet
– Exercise
– Pharmacotherapy
• Summary
11
ARS: Which intervention was most
effective in reducing the risk of diabetes
among those at risk in the DPP?
1. Diet and exercise
2. Metformin
12
DPP Results: 3.2-Year Progression
from IGT to T2DM
58% reduction
IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus.
Knowler WC et al. N Engl J Med. 2002;346(6):393–403.
14
ARS: A reduced-calorie diet emphasizing
which of the following is associated with
the greatest weight loss?
1. Carbohydrate
2. Fat
3. Protein
4. No difference
15
POUNDS LOST: Weight Loss (ITT)
Diet Composition
Carbohydrate/Protein/Fat
0
–1
65/15/20
55/25/20
45/15/40
35/25/40
Weight Loss (kg)
–2
–3
–4
–5
–6
–7
0
6
12
18
24
Months
ITT, intent to treat.
Sacks FM et al. N Engl J Med. 2009;360(9):859–873.
17
POUNDS LOST: Weight Change and
Attendance: High Protein, High Fat
30
Weight Change (kg)
20
10
0
–10
–20
–30
–40
–50
0
10
20
30
40
N = 168
Number of Sessions Attended
Slope = –0.217
P < 0.001
Sacks FM et al. N Engl J Med. 2008;360(9):859–873.
50
60
18
Dietary Components That Predict
4-Year Changes in Body Weight
Weight effects, lb
Whole grains
Vegetables
Fruits
Nuts
Yogurt
Fried foods home
Trans fat
Processed meats
Red meats
Sugared beverage
Potato fries
Potato chips
Mozafferian D et al. N Engl J Med. 2011;364(25):2392–2404.
19
Key Points
• Weight loss is beneficial
• Several strategies will produce weight loss
– Lifestyle changes
– Diet
– Exercise
– Pharmacotherapy
• Summary
20
Effect of Exercise on Initial Rate of Weight
Loss and on Subsequent Weight Status
Non-Exercise
8
Exercise
Treatment (weeks)
Pavlou KN et al. Am J Clin Nutr. 1989;49(5 suppl):1110–1114.
18
Follow-up (months)
21
High Activity Needed for Weight Loss
Maintenance
P Values
Group effect <0.001
Time effect <0.001
Group X time effect <0.02
–2
–4
–6
Change in Weight (kg)
Percent Weight Loss (%)
0
–8
–10
–12
–14
–16
0
6
12
18
24
Months
<150 min/wk (N = 86)
250–299 min/wk (N = 21)
150–249 min/wk (N = 19)
≥300 min/wk (N = 44)
*P<0.05.
Jakicic JM et al. Arch Intern Med. 2008;168(14):1550–1560.
22
Key Points
• Weight loss is beneficial
• Several strategies will produce weight loss
– Lifestyle changes
– Diet
– Exercise
– Pharmacotherapy
• Summary
23
Pharmacotherapy
• For obesity without comorbidities
• For obesity with diabetes mellitus
• Drugs in limbo
24
Drugs Approved by the FDA for Treatment
of Obesity
• Sympathomimetics
– Diethylpropion (DEA Schedule IV)
– Phentermine (DEA Schedule IV)
– Benzphetamine (DEA Schedule III)
– Phendimetrazine (DEA Schedule III)
• Orlistat
FDA, Food and Drug Administration; DEA, Drug Enforcement Administration
.
25
Effect of Long-term Treatment With Orlistat
(The XENDOS Study)
Change in Body Weight (kg)
0
–3
Placebo + Lifestyle
P<0.001
–6
Orlistat + Lifestyle
–9
–12
0
52
104
156
208
Weeks of Treatment
Torgerson JS et al. Diabetes Care. 2004;27(1):155–161.
26
Pharmacotherapy
• For obesity without comorbidities
• For obesity with diabetes mellitus
• Drugs in limbo
27
ARS: Which of the following classes
of drugs for patients with diabetes is
associated with weight loss?
1. DPP-4 inhibitors
2. GLP-1 agonists
3. Insulin
4. Sulfonylureas
5. Thiazolidinediones
DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1.
28
Slide Unavailable
Bray, Circulation in press
30
DPP: Metformin and Lifestyle Over Time
2
Change in Weight (kg)
0
–2
–4
Placebo
Metformin
–6
Lifestyle
–8
0
1
2
3
4
5
6
7
8
9
10
Year Since DPP Randomization
DPP Research Group. Lancet. 2009;374(9702):1677–1686.
31
Pramlintide Produced Weight Loss:
% Change in Weight (ITT Populations,
Observed Data)
BID Regimen
TID Regimen
Evaluable
1
Double-blind study
ITT-LOCF
Evaluable
1
Single-blind extension
ITT-LOCF
Single-blind extension
0
-1
-2
-3
-4
-5
-6
*
*
-7
-8
**
-9
-10
Mean (±SE) Change in Body Weight (kg)
Mean (±SE) Change in Body Weight (kg)
0
Double-blind study
-1
-2
-3
-4
-5
*
-6
*
*
**
**
**
*
**
-7
-8
-9
-10
-11
-11
0
Number of Subjects
Placebo
36
120 µg BID 38
240 µg BID 32
360 µg BID 39
4
36
38
32
39
Placebo
Time (mo)
17
24
17
21
8
17
25
16
21
120 µg Pramlintide
12
17
24
17
21
12
27
28
25
32
0
Number of Subjects
Placebo
36
120 µg BID 38
240 µg BID 45
360 µg BID 42
4
36
38
45
42
240 µg Pramlintide
*P < 0.05 and **P < 0.01 for each pramlintide treatment group versus placebo.
Smith SR et al. Diabetes Care. 2008;31(9):1816–1823.
Time (mo)
17
25
23
18
8
12
12
17
25
23
18
17
25
23
17
27
29
30
38
360 µg Pramlintide
32
Combination of Pramlintide and
Phentermine on Body Weight
0
Weight Loss (kg)
Placebo
Pramlintide
–5
–10
Pram + Phen
–15
0
10
20
30
Weeks of Treatment
Aronne L et al. Obesity (Silver Spring). 2010;18(9):1739–1746.
33
Exenatide:* An Anti-diabetic Drug That
Produces Weight Loss
Change in body weight (kg)
0.5
0
-0.3 ± 0.3 kg
-0.5
**
-1.0
**
-1.5
-1.6 ± 0.4 kg
†
**
-2.0
-2.5
†
Placebo
5 g Exenatide
10 g Exenatide
-3.0
-3.5
-2.8 ± 0.5 kg
†
†
†
-4.0
0
5
10
15
Weeks
*Not approved for treatment of obesity
**P≤.05 vs placebo; †P≤.001 vs placebo.
Defronzo RA, et al. Diabetes Care. 2005;28:1092-1100.
20
25
30
Liraglutide,* an Antidiabetic Drug, and
Orlistat Produce Weight Loss
0
Placebo
1.2 mg/day
–4
–6
1.8 mg/day
Randomization
Screening
Weight Loss (kg)
–2
2.4 mg/day
3.0 mg/day
Orlistat
–8
–10
–5
0
5
10
15
20
Weeks From Randomization
*Not approved for treatment of obesity.
Astrup A et al. Lancet. 2009;374(9701):1606–1616.
35
Pharmacotherapy
• For obesity without comorbidities
• For obesity with diabetes mellitus
• Drugs in limbo
– Topiramate/phentermine
– Bupropion/naltrexone
– Lorcaserin
36
Topiramate/Phentermine* Produces
Weight Loss (Completers)
0
Weight change (kg)
-2
-4
*
-6
*
Placebo
Phentermine 7.5 mg plus topiramate 46.0 mg
Phentermine 15.0 mg plus topiramate 92.0 mg
*
*
-8
*
*
*
*
*
*
*
16
24
32
40
Weeks of Treatment
48
56
851
437
744
403
670
387
623
369
589
356
573
350
557
338
843
775
747
712
686
660
625
*
-10
*
*
-12
-14
0
Study completers
Placebo 979
Phentermine 7.5 mg plus 488
topiramate 46.0 mg
Phentermine 15.0 mg plus 981
topiramate 92.0 mg
8
*Investigational
Gadde KM et al. Lancet. 2011;377(9774):1341–1352.
37
Naltrexone-Bupropion* Produces Weight
Loss (Completers)
Weight Change from Baseline (kg)
0
Placebo
N = 507
–2
–4
–6
NB 16 mg (N = 467)
–8
NB 32 mg (N = 467)
–10
0
8
16
24
32
40
48
56
Bupropion 360 mg/day
Dropouts ̴ 50%
Weeks of Treatment
*Investigational
Greenway FL et al. Lancet. 2010;376(9741):595–605.
38
Lorcaserin* Produces Weight Loss
(Completers)
0
Weight Loss (kg)
–2
–4
Placebo
Crossover
–6
Continuous
–8
–10
–12
0 8 16 24 32 40 48 56 64 72 80 88 96 104
Weeks of Treatment
*Investigational
Placebo N = 684
Crossover N = 275
Continuous N = 564
Smith SR et al. N Engl J Med. 2010; 363(3):245–256.
39
Key Points
• Weight loss is beneficial
• Several strategies will produce weight loss
– Lifestyle changes
– Diet
– Exercise
– Pharmacotherapy
• Summary
40
Summary and Recapitulation
• Weight loss is beneficial, particularly if disease risk
is present
• Several strategies will produce weight loss
– Lifestyle changes/diet/exercise
– Pharmacotherapy
– Surgery
• Summary
41
2010 Was A Momentous & Disappointing
Year for Obesity With 5 FDA Panels
• July 15, 2010 – Combination of topiramate/ phentermine
reviewed by FDA - 10 for 6 against
• Sept 15, 2010 – Continued marketing of sibutramine in light
of SCOUT study was reviewed by FDA panel - 8 for and 8
against continued marketing
• Sept 16, 2010 – Lorcaserin new drug application reviewed
by FDA Panel – 9 for and 5 against
• Oct 8, 2010 – Sibutramine withdrawn
• Dec 7, 2011 – BMI lowered for some surgical operations
• Dec 15, 2010 – Combination of buproprion/ naltrexone
recommended 13/7 for approval. FDA is requiring an
outcomes trial before approval
Unintended Consequences of Drug
Treatment for Obesity in the 20th Century
Year
Drug
Consequence
1892
Thyroid
Hyperthyroidism
1932
Dintrophenol
Cataracts/Neuropathy
1937
Amphetamine
Addiction
1968
Aminorex
Pulmonary Hypertension
1997
Phen/Fenfluramine
Valvulopathy
1998
Phenylpropanolamine
Strokes
2003
Ma Huang (ephedra)
Heart attacks/stroke
2007
Ecopipam (Dopamine)
Depression/Suicide
2008
Rimonabant (CB-1)
Depression
2010
Sibutramine
CVD Risk
Bray GA Battle of the Bulge, Dorrance Publishing 2007 p. 59
Lesson for Today
• “A desire to take medicine is, perhaps, the great feature
which distinguishes man from other animals”
Osler W. Science 1891;17:170-171