George A. Bray, MD, MACE

1
Comprehensive Approaches to Intervention
George A. Bray, MD, MACE Pennington Biomedical
Research Center Louisiana State University Baton
Rouge, Louisiana
2
Key Points

• Weight loss is beneficial
• Several strategies will produce weight loss
• Lifestyle changes
• Diet
• Exercise
• Pharmacotherapy
• Summary

3
BMI Has Biggest Effect on Diabetes
Men
Women
Relative Risk
Relative Risk
lt21
22
23
24
25
26
27
28
29
30
lt21
22
23
24
25
26
27
28
29
30
BMI (kg/m2)
BMI (kg/m2)
Type 2 diabetes Cholelithiasis
Hypertension Coronary heart disease
BMI, body mass index. Willett WC et al. N Engl J
Med. 1999341(6)427434.
4
Small Weight Loss Reduces Risk of Diabetes in the
DPP
Placebo
Reduces Risk of Diabetes by 58
Lifestyle
Weight Change in DPP (kg)
0
6
12
18
24
30
36
42
48
Months in Study
DPP, Diabetes Prevention Program. Knowler WC et
al. N Engl J Med. 2002346(6)393403.
5
How Much Weight Loss Is Needed to Prevent Type 2
Diabetes?
Redrawn from Hamman RF et al. Diabetes Care.
200629(9)21022107.
6
Key Points

• Weight loss is beneficial
• Several strategies will produce weight loss
• Lifestyle changes
• Diet
• Exercise
• Pharmacotherapy
• Summary

7
Components of Behavior Therapy for Obesity
Problem solving
Self-monitoring
Cognitive restructuring
Contingency management
Obesity
Social support
Stimulus control
Stress management
Wadden TA, Foster GD. Med Clin North Am.
200084(2)441461.
8
4-Year Weight Loss in the Look AHEAD Trial
Weight Change From Baseline ()
DSE ILI
Year
Repeated measures adjusted for clinic and
baseline level. P value for average effect across
all visits P lt 0.0001. DSE, diabetes support and
education ILI , intensive lifestyle
intervention. Look AHEAD Research Group, Wing RR.
Arch Intern Med. 2010170(17)15661575.
9
Lifestyle Intervention Was Clinically Effective
in All Subsets of an Ethnically and
Demographically Diverse Population
Non-Hispanic White
Other/Mixed
African American
Hispanic
0.0
2.0
Male Female
4.0
Reduction () in Initial Weightin ILI
Participants
6.0
8.0
10.0
12.0
Wadden TA et al. Obesity (Silver Spring).
200917(4)713722.
10
Correlates of Weight Loss Look AHEAD

• Rank Order of Importance
• Self-reported physical activity
• Diet and physical activity counseling sessions
  attended
• Consumption of meal replacements
• At 1 year, ILI participants lost more weight if
• Attended more treatment sessions
• Exercised more
• Consumed more meal replacement products

11
Key Points

• Weight loss is beneficial
• Several strategies will produce weight loss
• Lifestyle changes
• Diet
• Exercise
• Pharmacotherapy
• Summary

12
ARS Which intervention was most effective in
reducing the risk of diabetes among those at risk
in the DPP?
?

• Diet and exercise
• Metformin

13
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14
DPP Results 3.2-Year Progressionfrom IGT to
T2DM
58 reduction
IGT, impaired glucose tolerance T2DM, type 2
diabetes mellitus.Knowler WC et al. N Engl J
Med. 2002346(6)393403.
15
ARS A reduced-calorie diet emphasizing which of
the following is associated with the greatest
weight loss?
?

• Carbohydrate
• Fat
• Protein
• No difference

16
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POUNDS LOST Weight Loss (ITT)
0
1
2
3
Weight Loss (kg)
4
5
6
7
0
6
12
18
24
Months
ITT, intent to treat.Sacks FM et al. N Engl J
Med. 2009360(9)859873.
18
POUNDS LOST Weight Change and Attendance High
Protein, High Fat
30
20
10
0
10
Weight Change (kg)
20
30
40
50
0
10
20
30
40
50
60
N 168 Slope 0.217 P lt 0.001
Number of Sessions Attended
Sacks FM et al. N Engl J Med. 2008360(9)859873.
19
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.
2011364(25)23922404.
20
Key Points

• Weight loss is beneficial
• Several strategies will produce weight loss
• Lifestyle changes
• Diet
• Exercise
• Pharmacotherapy
• Summary

21
Effect of Exercise on Initial Rate of Weight Loss
and on Subsequent Weight Status
Pavlou KN et al. Am J Clin Nutr. 198949(5
suppl)11101114.
22
High Activity Needed for Weight Loss Maintenance
P Values Group effect lt0.001 Time effect
lt0.001 Group X time effect lt0.02
0
2
4
6
Percent Weight Loss ()
8
10
12
Change in Weight (kg)
14
16
0
6
12
18
24
Months
Plt0.05.
Jakicic JM et al. Arch Intern Med.
2008168(14)15501560.
23
Key Points

• Weight loss is beneficial
• Several strategies will produce weight loss
• Lifestyle changes
• Diet
• Exercise
• Pharmacotherapy
• Summary

24
Pharmacotherapy

• For obesity without comorbidities
• For obesity with diabetes mellitus
• Drugs in limbo

25
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.
26
Effect of Long-term Treatment With Orlistat (The
XENDOS Study)
0
3
Placebo Lifestyle
Plt0.001
6
Change in Body Weight (kg)
Orlistat Lifestyle
9
12
0
52
104
156
208
Weeks of Treatment
Torgerson JS et al. Diabetes Care.
200427(1)155161.
27
Pharmacotherapy

• For obesity without comorbidities
• For obesity with diabetes mellitus
• Drugs in limbo

28
ARS Which of the following classes of drugs for
patients with diabetes is associated with weight
loss?
?

• DPP-4 inhibitors
• GLP-1 agonists
• Insulin
• Sulfonylureas
• Thiazolidinediones

DPP-4, dipeptidyl peptidase-4 GLP-1,
glucagon-like peptide-1.
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Slide Unavailable
Bray, Circulation in press
31
DPP Metformin and Lifestyle Over Time
DPP Research Group. Lancet. 2009374(9702)167716
86.
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Pramlintide Produced Weight Loss Change in
Weight (ITT Populations, Observed Data)
BID Regimen
TID Regimen
Evaluable
ITT-LOCF
Evaluable
ITT-LOCF
1
1
Single-blind extension
Double-blind study
Single-blind extension
Double-blind study
0
0
-1
-1
-2
-2
-3
-3
-4
-4
-5
Mean (SE) Change in Body Weight (kg)
-5
Mean (SE) Change in Body Weight (kg)

-6
-6







-7
-7


-8
-8

-9
-9
-10
-10
-11
-11
0
4
8
12
12
0
4
8
12
12
Time (mo)
Time (mo)
Number of Subjects Placebo 36 120 µg BID 38 240
µg BID 32 360 µg BID 39
Number of Subjects Placebo 36 120 µg BID 38 240
µg BID 45 360 µg BID 42
36 17 38 24 32 17 39 21
17 25 16 21
17 24 17 21
27 28 25 32
36 17 38 25 45 23 42 18
17 25 23 18
17 25 23 17
27 29 30 38
P lt 0.05 and P lt 0.01 for each pramlintide
treatment group versus placebo. Smith SR et al.
Diabetes Care. 200831(9)18161823.
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Combination of Pramlintide and Phentermine on
Body Weight
0
Placebo
Pramlintide
5
Weight Loss (kg)
10
Pram Phen
15
0
10
20
30
Weeks of Treatment
Aronne L et al. Obesity (Silver Spring).
201018(9)17391746.
34
Exenatide An Anti-diabetic Drug That Produces
Weight Loss
0.5
0
-0.3 0.3 kg
-0.5

-1.0

-1.5
-1.6 0.4 kg

Change in body weight (kg)

-2.0
-2.5

Placebo
-2.8 0.5 kg

-3.0
5 ?g Exenatide

10 ?g Exenatide

-3.5
-4.0
0
5
10
15
20
25
30
Weeks
Not approved for treatment of obesity P.05 vs
placebo P.001 vs placebo. Defronzo RA, et al.
Diabetes Care. 2005281092-1100.
35
Liraglutide, an Antidiabetic Drug, and Orlistat
Produce Weight Loss
Not approved for treatment of obesity. Astrup A
et al. Lancet. 2009374(9701)16061616.
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Pharmacotherapy

• For obesity without comorbidities
• For obesity with diabetes mellitus
• Drugs in limbo
• Topiramate/phentermine
• Bupropion/naltrexone
• Lorcaserin

37
Topiramate/Phentermine Produces Weight Loss
(Completers)
0
-2
-4
Placebo Phentermine 7.5 mg plus topiramate 46.0
mg Phentermine 15.0 mg plus topiramate 92.0 mg


-6

Weight change (kg)

-8





-10



-12


-14
0
8
16
24
32
40
48
56
Weeks of Treatment
Study completers Placebo Phentermine 7.5 mg
plus topiramate 46.0 mg Phentermine 15.0 mg
plus topiramate 92.0 mg
979 488 981
851 437 843
744 403 775
670 387 747
623 369 712
589 356 686
573 350 660
557 338 625
Investigational Gadde KM et al. Lancet.
2011377(9774)13411352.
38
Naltrexone-Bupropion Produces Weight Loss
(Completers)
Bupropion 360 mg/day Dropouts ? 50
Investigational Greenway FL et al. Lancet.
2010376(9741)595605.
39
Lorcaserin Produces Weight Loss (Completers)
0
2
Placebo
Crossover
4
Continuous
Weight Loss (kg)
6
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)245256.
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Key Points

• Weight loss is beneficial
• Several strategies will produce weight loss
• Lifestyle changes
• Diet
• Exercise
• Pharmacotherapy
• Summary

41
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

42
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

43
Unintended Consequences of Drug Treatment for
Obesity in the 20th Century
Bray GA Battle of the Bulge, Dorrance Publishing
2007 p. 59
44
Lesson for Today

• A desire to take medicine is, perhaps, the great
  feature which distinguishes man from other
  animals

Osler W. Science 189117170-171