Obesity Treatment Pyramid
Surgery
Pharmacotherapy
Lifestyle Modification
Diet
Physical Activity
Slide Source:
www.obesityonline.org
Guide for Selecting Obesity Treatment
BMI Category (kg/m2)
Treatment
25-26.9
27-29.9
30-34.9
35-39.9
>40
Diet,
Exercise,
Behavior Tx
+
+
+
+
+
With comorbidities
+
+
+
With comorbidities
+
Pharmacotherapy
Surgery
The Practical Guide: Identification, Evaluation, and Treatment of
Overweight and Obesity in Adults. October 2000, NIH Pub. No.00-4084
Slide Source:
www.obesityonline.org
Obesity and Dietary Therapy
“Duct Tape”
Slide Source:
www.obesityonline.org
Short-term Obesity Therapy Does Not
Result in Long-term Weight Loss
Change in Weight (kg)
5
0
Diet alone
Behavior therapy
Combined therapy
-5
-10
-15
-20
Baseline
End of
Treatment
Wadden et al. Int J Obes 1989;13 (Suppl 2):39.
1-year
Follow-up
5-year
Follow-up
Slide Source:
www.obesityonline.org
Slide Source:
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Sustained Weight Loss Can Be Achieved
with Behavior Modification Therapy
Active Treatment
No Active Treatment
Weight Loss (kg)
0
-5
Women
-10
-15
-20
Men
-25
-30
-35
0
2
4
6
8
10-12
Years
Björvell and Rössner. Int J Obes Relat Metab Disord 1992;16:623.
Slide Source:
www.obesityonline.org
Cardinal Behaviors of Successful Long-term
Weight Management
National Weight Control Registry Data

Self-monitoring:
– Diet: record food intake daily, limit certain foods or
food quantity
– Weight: check body weight >1 x/wk

Low-calorie, low-fat diet:
– Total energy intake:
1300-1400 kcal/d
– Energy intake from fat: 20%-25%

Eat breakfast daily

Regular physical activity: 2500-3000 kcal/wk
(eg, walk 4 miles/d)
Klem et al. Am J Clin Nutr 1997;66:239.
McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.
Slide Source:
www.obesityonline.org
Principles of Pharmacotherapy
in the Management of Obesity
Slide Source:
www.obesityonline.org
Regulation of Food Intake
External factors
Brain
Central Signals
Stimulate
Inibit
NPY
Orexin-A
AGRP Dynorphin
galanin ECS/CB1
α-MSH
CART
CRH/UCN NE
GLP-I
5-HT
Peripheral signals
Glucose

CCK, GLP-1,
Apo-A-IV
Vagal afferents
Peripheral organs
Gastrointestinal
tract
Food
Intake
Insulin
+

+
Ghrelin
Emotions, Drugs
Food characteristics
Lifestyle behaviors
Environmental cues
Leptin
Adipose
tissue
Cortisol
Adrenal glands
Slide Source:
www.obesityonline.org
Drugs Approved by FDA for Treating Obesity
Trade
Names
DEA
Schedule
Approved
Use
Year
Approved
Orlistat
Xenical
None
Long-term
1999
Sibutramine
Meridia
IV
Long-term
1997
Diethylpropion
Tenulate
IV
Short-term
1973
Phentermine
Adipex,
lonamin
IV
Short-term
1973
Phendimetrazine
Bontril,
Prelu-2
III
Short-term
1961
Benzphetamine
Didrex
III
Short-term
1960
Generic Name
Slide Source:
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Meta-analysis of RCTs Evaluating Effect of
Orlistat Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
*All subjects had type 2 diabetes
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-10
-5
0
Favours
Treatment
5
Favours
Control
10
Slide Source:
www.obesityonline.org
Effect of Long-term Orlistat Therapy on
Body Weight
Change in Weight (kg)
0
-3
-4.1 kg
Placebo
-6
-6.9 kg
-9
Orlistat
P<0.001 vs placebo
-12
0
52
104
Weeks
Torgenson et al. Diabetes Care 2004;27:155
156
208
Slide Source:
www.obesityonline.org
Gastrointestinal Side Effects of Orlistat Therapy
Year 1
Placebo
Fatty/oily stool
Increased defecation
Liquid stools
Fecal urgency
Flatulence
Flatus with discharge
Fecal incontinence
Oily evacuation
Low plasma vitamin conc:
Vitamin A
Vitamin D
Vitamin E
Year 2
Orlistat
Placebo
Orlistat
5
7
10
3
3
0
0
1
31
20
13
10
7
7
7
6
1
2
5
2
2
0
0
0
8
2
8
3
3
1
2
5
0.6
0.6
0.9
0.3
5.1
4.6
0.8
0.8
0
0
3.1
1.6
Values are percentage of subjects.
Sjostrom et al. Lancet 1998;352:167.
Slide Source:
www.obesityonline.org
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study
or Sub-category
WMD (random)
95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
-10
•All subjects had hypertension
WMD=weighted mean difference
Padwal et al. Int J Obes 2003;27:1437
-5
0
Favours
Treatment
5
Favours
Control
10
Slide Source:
www.obesityonline.org
Effect of Continuous vs Intermittent Subutramine
Therapy on Body Weight
Body Weight Change (kg)
0
Placebo
Intermittent sibutramine
Continuous sibutramine
-2
-4
-6
-8
-10
Run-in
period
0
4
8
12
Sibutramine dose=15 mg/d.
16
20 24 28 32
Time (wk)
Wirth and Krause. JAMA 2001;286:1331.
36 40
44
48
Slide Source:
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Adverse Effects of Sibutramine Therapy
Adverse Effect
Subjects (%)
Placebo
Sibutramine
Headache
18.6
30.3
Dry mouth
4.2
17.2
Constipation
6.0
11.5
Insomnia
4.5
10.7
Dizziness
3.4
7.0
Hypertension
0.9
2.1
Tachycardia
0.6
2.6
Palpitation
0.8
2.0
Meridia™ Package Insert, 2001.
Slide Source:
www.obesityonline.org
Effect of Continuous and Intermittent
Phentermine Therapy on Body Weight
0
Weight Loss (lbs)
-4
Continuous
Dummy
-8
-12
-16
-20
-24
Alternate Phentermine
and Dummy QOM
-28
-32
0
4
8
12 16 20 24
Time (weeks)
Munro JF et al. Brit Med J 1:352, 1968
Continuous
Phentermine
28
32
36
Slide Source:
www.obesityonline.org
Regulation of Food Intake
External factors
Brain
Central Signals
Stimulate
Inibit
NPY
Orexin-A
AGRP Dynorphin
galanin ECS/CB1
α-MSH
CART
CRH/UCN NE
GLP-I
5-HT
Peripheral signals
Glucose

CCK, GLP-1,
Apo-A-IV
Vagal afferents
Peripheral organs
Gastrointestinal
tract
Food
Intake
Insulin
+

+
Ghrelin
Emotions, Drugs
Food characteristics
Lifestyle behaviors
Environmental cues
Leptin
Adipose
tissue
Cortisol
Adrenal glands
Slide Source:
www.obesityonline.org
Gastrointestinal Peptides Hormones
food intake regulation
Vagus
nerve
Anti-obesity potential
digestion and metabolism
Ghrelin
Leptin
Insulin
Amylin
Glucagon
PYY
CCK
Anti-diabetes potential
GLP-1
Modified from Marx, Science 2003 February 7; 299: 846-849. (in News)
Slide Source:
www.obesityonline.org
GLP-1

GLP-1: incretin hormone

Exenatide (Byetta); incretin mimetic
–
–
–
–
–
Enhances insulin secretion
Suppresses elevated glucagon secretion
Reduces food intake and body weight
Slows gastric emptying
Increase in beta-cell mass
Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001; 86:3717-3723
Drucker DJ. Mol Endocrinol 2003; 17:161-171
Nielsen LL, et al. Reg Pept 2004; 117:77-88
Slide Source:
www.obesityonline.org
Neuroendocrinology of Food Intake Regulation
Hindbrain as a Target for Peripheral Satiety Signals
Area Postrema:
• part of dorsal vagal complex
• chemoreceptive (no BBB)
• site of neural integration
Hypothalamus
• bi-directional projections to
the GI tract (via vagal
afferents and efferents)
ARC
• bi-directional projections to
the hypothalamus, amygdala
and other regions
NTS/AP
Vagus
CCK
GhrelinPYY Leptin
Insulin
GI tract
Spinal
nerves
Amylin
other circulating gut peptides
Modified from Marx, Science 2003 February 7; 299: 846-849. (in News)
Safety and Tolerability
Exenatide Open-Label Extensions

Exenatide generally well tolerated

Adverse events
– Nausea (30-40%)
– Diarrhea (7%)
– Vomiting (9%)
– Feeling jittery (5%)
– Dizziness (3%)
– Headache (3%)
Slide Source:
www.obesityonline.org
Amylin:
A Neuroendocrine Hormone
Amylin Receptor
Identified
N
N
Amylin Binding Sites in the Brain
Dorsale Raphe
C
RAMP
1 or 3
Nucleus Accumbens
Beaumont K, et al. Mol Pharm 1993; 44:493-497
Adapted from Muff R, et al. Endocrinology1999; 140:2924-2927
Area Postrema
C
CTR
Effects of Pramlintide in Type 2 Diabetes
Pooled 120 µg BID Pramlintide Intent to Treat Populations
Placebo + Insulin
120 µg Pramlintide
Change in Insulin Use (%)
Change in A1C (%)
Week 4
Week 13
Week 26
Week 4
0
6
-0.1
5
-0.2
4
-0.3
3
2
-0.4
-0.5
1
0
-0.6
-1
-0.7
-2
-0.8
-3
Placebo + Insulin (N=284; Baseline A1C 9.3%)
120 µg Pramlintide BID Dose + Insulin (N=292;
Baseline A1C 9.1%)
Data on file, Amylin Pharmaceuticals, Inc.
Week 13
Change in Weight (lb)
Week 26
Week 4
2.5
2.0
1.5
1.0
0.5
0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
Week 13
Week 26
Slide Source:
www.obesityonline.org
Endocannabinoid System (CB-1) as a Potential Target of
Action for Modulation of Energy Homeostasis and Obesity
Energy Balance
Feeding Behavior
Hypothalamus
Hunger/satiety
Gastric emptying
GI motility
Limbic forebrain
Motivation for
palatable food
Hepatic glucose output
Lipogenesis
Ghrelin, PYY
Hepatic Lipogenesis
Adipose Tissue Metabolism
Glucose Homeostasis
Glucose uptake
Glucose, lipid oxidation
Lipolysis
Lipogenesis
Slide Source:
www.obesityonline.org
27
28
The ECS is Overactivated in:
 Animal models of genetic
obesity
 Animal models of diet-induced
obesity
 Human obesity
Slide Source:
www.obesityonline.org
Endocannabinoids Stimulate
Food Intake in Mice
7
29
Anandamide 0.001 mg/kg
*P<0.05; **P<0.01 vs vehicle
Vehicle
*
6
Food intake
(grams/day)
*
**
5
*
4
3 1
3
5
7
Day
Hao S et al. Eur J Pharmacology. 2000; 392:147-156.
Slide Source:
www.obesityonline.org
30
The ECS is Upregulated in Human Obesity
2
1
30
*
20
10
CB1 Receptor
80
*
60
40
20
Lean
0
Lean
Obese
FAAH
10.0
7.5
5.0
*
2.5
0.0
0
0
Lean Obese
100
FAAH/GAPDH [AUl]
*
CB1 Receptor and FAAH Gene Expression in
Adipose Tissue of Lean and Obese Women
CB1/GADPH [AU]
3
2-AG [pmol/mL]
AEA [pmol/mL]
Circulating Endocannabinoid Levels
are Higher in Obese vs Lean Women
Obese
Lean
Obese
Reduced CB1 receptors in the obese women may
reflect negative feedback to increased endogenous
ligands seen in classical hormone –receptor
relationship
* P<0.05 vs lean women
Engeli S, et al. Diabetes 2005; 54:2838–2843.
Slide Source:
www.obesityonline.org
31
A Mutation in the Enzyme That Degrades
Endocannabinoids is Associated with Increased BMI
% of subjects with FAAH 385 A/A
Percent of subjects with FAAH 385 A/A genotype by BMI category
* vs normal BMI
10
16
Caucasians
African Americans
14
8
P<0.01*
P<0.05*
6
P<0.05*
12
10
4
8
2
5
0
4
18.5-24.9
25.0-29.9
>30.0
18.5-24.9
BMI (kg/m2)
Sipe JC et al. Int J Obes Relat Metab Disord.2005;29:755-759.
25.0-29.9
>30.0
BMI (kg/m2)
Slide Source:
www.obesityonline.org
CB1 Blockade Produces a Dose-Related Reduction in
Food Intake in Mice
32
2.0
1.5
Food
intake 1.0
(g)
0.5
0.0
0.0
0.3
1.0
3.0
10.0
Rimonabant Dose (mg/kg-1)
Wiley JL et al. Br J Pharmacol. 2005;145:293-300.
Slide Source:
www.obesityonline.org
33
Supporting Evidence:

Adipose tissue metabolism
–
–
–
–
EC stimulation with CB1 agonist increases
adipose tissue LPL expression while CB1
blockade inhibits this effect
CB1 stimulation reduces while blockade
increases adiponectin synthesis
CB1 blockade reverses the histological changes
in adipose tissue produced by diet-induced
obesity
EC stimulation reduces the expression of AMP
kinase in visceral fat
Cota D et al. J Clin Invest. 2003;112:423.
Matias I, et al. XV ICRS Symposium June 24-27, 2005; Clearwater, Fla.
Jbilo O, et al. FASEB J. 2005;19:1567-1569.
Slide Source:
www.obesityonline.org
34
The Peripheral ECS in Adipose Tissue
Adipose tissue
of obese mice
fed a high fat
diet (HFD) plus
rimonabant
resembles that
of lean mice fed
a standard diet
(STD)
Standard Diet
High Fat Diet
High Fat Diet +
Rimonabant
Jbilo O, et al. FASEB J. 2005;19:1567-1569.
Slide Source:
www.obesityonline.org
35
ECS Stimulation, Centrally and Peripherally,
Favors Metabolic Processes that Lead to:
 Weight Gain
 Lipogenesis
 Insulin Resistance
 Dyslipidemia
 Impaired Glucose Homeostasis
Slide Source:
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36
RIO: Rimonabant In Overweight/Obesity
CB-1 Blockade in Human Studies
(>6600 patients enrolled)
Study
Population
N=6627
Design
Obese or overweight
with/without comorbidities
(excluding diabetes)
3040
1+1 year
Re
Rerandomized
Obese or overweight
with/without comorbidities
(excluding diabetes)
1507
2 years
Obese or overweight with
untreated dyslipidemia
(excluding diabetes)
1033
1 year
Obese or overweight with type
2 diabetes
1047
1 year
Pi-Sunyer FX.Obes Res. 2004;12(suppl):08-OR, A27.
Slide Source:
www.obesityonline.org
37
RIO-Europe and RIO-Lipids:
Weight Change at 1 Year
Completers
ITT (LOCF)
0
-1.5
Weight change (kg)
-2.3
-2
-1.8
Placebo
Rimonabant
20 mg
-4
-3.6
-6
-6.6
-8.6
-8
-6.9
-8.6
-10
0
16
32
Weeks
Van Gaal et al. The Lancet 2005; 365: 1389-97.
Despres J-P, et al. N Engl J Med. 2005;353:2121-2134.
48
Placebo
Rimonabant
ITT
20 mg
LOCF
Slide Source:
www.obesityonline.org
38
RIO-NA: Weight Change over 2-Years
in Re-randomized Patients
Placebo
Rimonabant 20 mg/PLB
Rimonabant 20 mg
ITT (LOCF)
00
Weight
(Kg)
(Kg)
change
Weightchange
-2.3 kg ± 0.5
-2
-2
-3.2 kg ± 0.4
-4
-4
-6
-6
-7.4 kg ± 0.4
-8
-8
-10
-10
0 4 8 12 16
16 20 24
24 28 32
32 36 40
40 44 48
48 52 56
56 60 64
64 68 72
72 76 80
80 84 88
88 92 96
96 100104
104 LOCF
LOCF
Weeks
Weeks
Weight (kg) Change from Baseline over 2 Years (Mean +/- SEM)
Pi-Sunyer FX et al. JAMA 2006;295:761-775.
Slide Source:
www.obesityonline.org
39
RIO-NA: HDL-C and TG over 2 Years*
*Patients on same treatment for 2 years
Placebo
ITT, LOCF
Rimonabant 5 mg
Rimonabant 20 mg
HDL-cholesterol
Triglycerides
15
25
20
+14.1%
p<0.001
15
+8.4%
ns
10
+7.8%
5
0
Change in Triglycerides (%)
Change in HDL-cholesterol (%)
30
5
0
+4.0%
-5
-1.9%
24
48
72
104 LOCF
Weeks
Pi-Sunyer FX et al. JAMA 2006;295:761-775.
ns
p<0.001
-10
-15
0
+6.6%
10
0
24
48
72
104 LOCF
Weeks
Slide Source:
www.obesityonline.org
40
RIO-Lipids: Percent Change in HDL-C and TG Levels at 1
Rimonabant 20 mg
Year
Rimonabant 5 mg
Placebo
Completers
10
P<0.001
22.9
25
20
P=0.017
15
15.6
10
11.8
Change in TG (%)
Change in HDL-C (%)
30
5
0
-5
P<0.001
5
0
-20
0
12
24
36
52
-3.6
-10
-15
0
+0.4
-15.7
12
24
36
Week
Week
ITT, LOCF
Placebo : 11. 8%
R5 mg : 14.2% (ns v. placebo)
R20 mg : 19.1% (p< 0.001 v. placebo)
Placebo : 0.0. %
R5 mg : 1.2%
R20 mg :-12.6% (p < 0.001 v. placebo)
Despres J-P, et al. N Engl J Med. 2005;353:2121-2134.
Slide Source:
www.obesityonline.org
52
RIO-DIABETES
Results: Weight Changes
Placebo
Rimonabant
5 mg
Rimonabant
20 mg
Weight loss (kg)
- 1.4±0.2
- 2.3±0.2
- 5.3±0.3
<0.001
Decrease in waist
circumference (cm)
- 1.9±0.3
- 2.9±0.3
- 5.2±0.3
<0.001
% of patients with
weight loss ≥ 10%
2.0
6.2
16.4
<0.001
% of patients with
weight loss ≥ 5%
14.5
21.7
49.4
<0.001
End Point
Scheen A. Late Breaking Clinical Trials. ADA Scientific Session 2005.
P-value
PLB vs 20 mg
Slide Source:
www.obesityonline.org
42
RIO-NA: Overall Safety Year 1
Placebo
Rimonabant
5 mg
Rimonabant
20 mg
n = 607
n = 1214
n = 1219
Overall discontinuations
49.1 %
49.0 %
44.9 %
Subjects with any
adverse event
82.0 %
83.4 %
85.5 %
Subjects with any
serious adverse event
3.5 %
3.8 %
4.5 %
Subjects discontinued
due to adverse event
7.2 %
9.4 %
12.8 %
Pi-Sunyer FX et al. JAMA 2006;295:761-775.
Slide Source:
www.obesityonline.org
RIO-NA: Adverse Events Leading
To Drug Discontinuation in Year 1
43
Placebo
Rimonabant
(N=607)
(%)
5 mg
(N=1214)
(%)
20 mg
(N=1219)
(%)
2.3
3.6
6.2
Depressed mood disorders
1.3
2.1
2.2
Anxiety
0.3
0.6
1.0
Irritability
0
0.2
0.5
Insomnia
0.2
<0.1
0.5
1.0
1.2
2.2
Headache
0.3
0.3
0.5
Dizziness
0.2
0
0.7
0.7
0.7
1.6
0.2
0.2
0.9
Psychiatric disorders
Nervous system disorders
Gastrointestinal disorders
Nausea
According to MedDRA, in any rimonabant groups : in main SOCs (>=1% ) and in at least 6 patients (0.5%).
One patient may report several events
Pi-Sunyer FX et al. JAMA 2006;295:761-775.
Slide Source:
www.obesityonline.org
44
RIO-NA: Main Adverse Events Leading to Drug
Discontinuation in Year 2*
Placebo
Psychiatric disorders
Depressed mood disorders
Anxiety
Rimonabant
5 mg
20 mg
(N=298)
N (%)
(N=300)
N (%)
(N=333)
N (%)
4 (1.3)
6 (2.0)
7 (2.1)
3 (1.0)
4 (1.3)
4 (1.2)
0 (0)
1 (0.3)
2 (0.6)
*Patients receiving the same treatment for 2 years
Pi-Sunyer FX et al. JAMA 2006;295:761-775.
Slide Source:
www.obesityonline.org
Conclusions

Obesity is a chronic disease

Modest weight loss (5% -10% of body weight)
can have considerable medical benefits

Lifestyle change (diet and physical activity) is the
cornerstone of therapy

Pharmacotherapy can be useful in properly
selected patients

Bariatric surgery is the most effective therapy for
severe obesity
Slide Source:
www.obesityonline.org
Obese Patients Have Unrealistic Weight
Loss Goals
Outcome
Weight (lbs)
% Reduction
Initial
218
0
Dream
135
38
Happy
150
31
Acceptable
163
25
Disappointed
180
17
Foster et al. J Consult Clin Psychol 1997;65:79.
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