Management of Obisity

Investigations  Stratification
Front Line Clinical Applications

New Frontiers and Emerging Treatment Paradigms for
Optimizing Management of Obesity
Focus on Multimodal Interventions for Weight Loss and Novel
Pharmacological Strategies Targeting the Central Nervous System
Program Chairman
TIMOTHY CHURCH, MD, MPH, PhD
John S. McIlHenny Endowed Chair in Health Wisdom
Professor
Pennington Biomedical Research Center
Louisiana State University
Baton Rouge, LA
Distinguished Faculty
TIMOTHY CHURCH, MD, MPH, PhD – Program Chairman

Professor
Baton Rouge, LA
DONNA H. RYAN, MD
Professor and Associate Executive
Director for Clinical Research
Baton Rouge, LA
PATRICK M. O'NEIL, PhD

Professor of Psychiatry and Behavioral Sciences
Director, Weight Management Center
Medical University of South Carolina
President, The Obesity Society
Charleston, SC
Current Challenges and Barriers to

Optimizing Management of Obesity
A Year 2014 Status Report for the Primary Care

Physician and Clinical Subspecialist
Program Chairman
Professor
Baton Rouge, LA
Long-term Control of Obesity – 2013
2.5% 1% 0.05% Lifestyle

Surgery
Medications
Unmet Needs
1% =
750,000
U.S. adults
96%
Obesity by the Numbers
Overweight U.S. adults: 67%

U.S. adults with obesity: 33%
U.S. children with obesity: 17%
Annual U.S. health care expenditures

for obesity: > $ 200 billion
U.S. consumer expenditures for

weight loss products: > $ 50 billion
Daily deaths from obesity complications > 1,000

Disproportionate Increase in Severe Obesity
Today, more than 1.7 million US adults with BMI>50

Sturm R, Pub Health, 2007
Complications of Obesity
Metabolic
Structural
Inflammatory
Degenerative
Neoplastic
65+
Psychological
BMI and Risk of Type 2 Diabetes
100 93.2
Age-Adjusted Relative Risk
Men
75 Women
54.0
50 40.3 42.1
27.6
21.3
25 8.1 15.8
2.9 4.3 5.0 11.6
2.2 6.7
1.0 1.5 4.4
1.0 1.0
0
<22 <23 23 24 25 27 29 31 33 35+
- - - - - - -
23.9 24.9 26.9 28.9 30.9 32.9 34.9
Body Mass index (kg/m2)
Chan J et al. Diabetes Care 1994;17:961.
Colditz G et al. Ann Intern Med 1995;122:481.
Inflammation and Obesity
Causative
 Hypothalamic inflammation likely contributes to
altered energy storage set point and obesity
etiology
Consequential
 Obesity associated with autoimmune and
inflammatory disorders (including hypothyroidism)
 Excess fat storage associated with adipose
inflammation
 Microbiota changes in obesity affect innate
immunity
Obesity is Counterintuitive
 Hides in plain sight

• Most obesity NOT recognized by physicians or the
public
 NOT mainly in America
 Did NOT start in the past 30 years
 NOT a problem of eating too much
 NOT a single disorder

• Possibly 100 or more clinically meaningful subtypes
• This recognition is essential to solving the problem
Cause of Obesity
Historical view
 Lifestyle choice
 Characterological flaw (willpower, psychology)
Current perspective
 Complex physiology
 Epidemic from changes in modern environment
 Widely recognized as a disease
 Huge burden of associated illness – a cause of more than

60 medical disorders (including 12 types of cancer)
 Devastating effect on efficacy and quality of life
Weight and Energy Balance
By the laws of physics…
Food
Intake Energy
Expenditure
The Normal Physiology of Energy Balance
Hunter-Gatherer Hadza and Westerners Have Equal

Daily Energy Expenditure
“ We hypothesize that human daily energy expenditure may be an

evolved physiological trait largely independent of cultural differences.”
Pontzer H, et al., PLoS ONE 2012; 7: e40503

The Normal Physiology of Energy Balance
Average adults require approximately 800 kcal/day
Average adults consume 2000-2500 kcal/day

• Average adults therefore consume 2.5-3 times as much food as required
• Excess intake is available for physiological emergencies
Maintaining weight within 20 lbs. between ages 21 and 65

requires matching of intake and expenditure within 0.2%
• Corresponds to accuracy of 4-5 kcal/day
• Less than one-half potato chip
Maintenance of normal fat stores (and body weight) requires

precise disposal of 60-70% of ingested calories daily
Thus, daily energy balance is likely an evolved physiological trait
largely independent of cultural or behavioral differences.
Feedback Regulation of Energy Metabolism
Environmental
Sensory Organs sensing Muscle Liver
GI Tract Bone
Irisin?
Metabolic
activity and
Energy needs
stores
Food intake
Leptin Nutrient handling
Energy
expenditure
Adipose
tissue
Defense of a Body Fat Storage “Set Point”
3000
kcal / 24 hours
Energy Energy
Intake Expenditure
2500
(+) Energy Balance (–) Energy Balance
2000
20 25 30 35
Metabolic adaptation
Body Mass Index (kg/m2)
Adapted from Weigle, 1995
GI Regulation of Metabolic Function
Central Mechanisms
Appetite
Energy balance
Glucose metabolism
Gut Efferent
hormones neurons Body Weight
Metabolic Function
Liver
Pancreas
GI Tract
Nutrients
Weight Loss Curve
Sumithran et al. NEJM 2011; 365:1597-1604.

Gut Hormone Changes Persistently
Ghrelin Oppose Diet-induced Weight Loss
PYY
Amylin
CCK
Sumithran et al. NEJM 2011; 365:1597-1604.

Obesity: A Failure of Weight Regulation
Cortex
Genetics
HT
Development
GI Tract
Food intake
Leptin Energy expenditure
Nutrient handling
Environment Adipose tissue

Environmental Influences on Metabolism
Direct Influences
on Brain
CNS
Enterokines Myokines
GI Tract
Adipokines
Muscle
Influences Influences
Through Gut Fat
Through Muscle
Environmental Drivers to Obesity
(3) Stress and distress (4) Drugs

(direct impact on relevant areas of the brain) (accounts for up to 10%)
Cortex (1) Altered

(2) Decreased food supply
physical activity HT
(signaling more
(effects on muscle than calories)
GI Tract
more than calories) Muscle Food intake
Leptin Energy expenditure
Nutrient handling
Adipose tissue
Macroenvironmental Influences*
• 24-hour lifestyle
• Economic structure
• Time pressures
• Workload
• Loss of downtime
• Speed of life
• Global stressors
*Limited effect of individual action

Microenvironmental Influences*
• Types of nutrients
• Eating schedules
• Physical activity
• Sleep health
• Drugs and medications
• Local stressors
*Amenable to individual action

Original Obesity Treatment Pyramid
Surgery
Pharmacotherapy
Lifestyle Modification
Healthy Diet Physical Activity

Realistic Obesity Treatment Pyramid
200,000 (0.25%)
Surgery
2,000,000 (2.5%)
Pharmacotherapy
Lifestyle
Modification 72,000,000
(90%)
Stress
Management
Healthy Diet Physical Activity

Overall Treatment Strategy
Typical Algorithm
(Progress through algorithm as clinically required)
Self-directed Lifestyle Change
Professionally-directed Lifestyle Change
Add Medications
Weight Loss Surgery
Post-surgical Combination Therapies

The Heterogeneity of Obesity
There is broad variability in the weight loss

response to ALL therapies for obesity
 Specific lifestyle interventions
 Medications
 Surgery
Epidemiology and Clinical Approaches to

Obesity Management
What Do Trials, Algorithms, and Clinical Experience

Teach Us About Sequencing Treatment Approaches
for Obesity?
PATRICK M. O'NEIL, PhD

Professor of Psychiatry and Behavioral Sciences
Director, Weight Management Center
Medical University of South Carolina
President, The Obesity Society
Charleston, SC
Obesity Diagnosis
► Obesity is defined an excess of body fat

► Body fat is difficult to measure cheaply
► For people with average lifestyles, Body Mass
Index (BMI) has been the measure of obesity
► BMI = Wt in Kg divided by height in M squared
► BMI has been divided into categories
 18-25 is normal, 25-30 is overweight, 30-35 is
class I, 35-40 is class II, >40 is class III
Relationship Between Mortality and BMI
2.5
Men
Women
Mortality Ratio
2.0
1.5
1.0
Very Very
Low Moderate High
Low High
0
20 25 30 35 40
Body Mass Index, kg/m2
Data from Lew EA: Mortality and weight: insured lives and the American
Cancer Society studies. Ann Intern Med 103:1024-1029, 1985.
Mortality: Diastolic Blood Pressure
Mortality: Body Mass Index
BMI Classes are Poor at Estimating Risk
► The BMI classes assume that mortality and morbidity is proportional to BMI
► This is not necessarily true. There are very obese people who are otherwise
healthy.
► In other chronic diseases like cancer there is a staging system to estimate risk
► An obesity staging system may be a better approach to estimating medical risk of
obesity
EOSS Predicts Mortality in NHANES III
Padwal R, Sharma AM et al. CMAJ 2011

Edmonton Obesity Staging System (EOSS)
Stage 2
co-morbidity
Stage 1 m cto al moderate Stage 3
en m
fa ic
rs
d- a
k lin
da
moderate
o r ge
ris re-c
se
ga
ild
ve
n
p
se
re
ve
ild
r
m
end-
end-
nt
Stage 0 Stage 4
end-
nt
abse
nt
stag
Obesity
abse
stag
abse
stag
e
e
e
l
al
na
al
nt
dic
tio
Me
Me
nc
Fu
Sharma AM & Kushner RF, Int J Obes 2009

Edmonton Obesity Staging System
► Stage 0: No obesity related risk factors

► Stage 1: Subclinical risk factors – borderline HTN or DM, minor aches or
psychopathology
► Stage 2: Established obesity-related disease – HTN, DM, PCO, moderate limitations ADL
► Stage 3: Established organ damage – MI, CHF, DM comp, significant limitations of ADL
► Stage 4: Severe disabilities – end stage and limitations like wheelchair use
Sharma AM and Kushner RF. Int J Obes. 2009;33:289-95

EOSS Predicts Mortality at Every BMI Level
NHANES III
Overweight

EOSS Distribution Across BMI Categories
NHANES III (1988-1994)
Overweight 23 million
10 million Class
III
50 million
6 million

Obesity is Leveling in Prevalence
► The prevalence of obesity in 1961 was 10%

in men and 15% in women defined as BMI
>30
► Obesity prevalence started to rise in 1980
► The prevalence of obesity is now leveling
off at 35.5% of the population.
► The prevalence of diabetes follows the
prevalence of obesity by approximately 10
years
► Diabetes prevalence started to rise in 1990
NHANES – Prevalence of Obesity
1961-2012
Work Related Physical Activity is Falling
Church TS et al. Plos One.2011;6(5):e19657

Fall in Energy Expenditure at Work
Mean Occupation
Related METs
1960 1970 1980 1990 2000 2010

Energy Expenditure (calories)
Occupation Related Daily
Year
1960 1970 1980 1990 2000 2010

Year
Church TS et al. Plos One.2011;6(5):e19657

Weight Gain Predicted by Activity
et al. Plos One.2011;6(5):e19657

What is Causing the Epidemic
► People are less active and are eating more

► There are many causes. We cannot just
scapegoat fast food
► Obesity virus – Adenovirus D-36 is one cause
► Endocrine disruptors have been suggested
► Regardless of the cause, eating less and being
more active will help – you will hear more in
this seminar on ways to accomplish that.
Another Cause of Obesity
► Adenovirus of D group 36 (AD-36) causes obesity in non-human primates

but one cannot intentionally infect humans
► AD-36 antibodies: 30% of obese and 11% lean
► In identical twins discordant for antibodies, the positive twin had 2.1% more
fat and had a BMI 1.4 units higher (p<0.03)
► This is insulin sensitive obesity with lower cholesterol and triglycerides
Atkinson RL et al. Int J. Obes. 2005;29(3):281-6

Is Obesity Prevalence Important?
► Obesity is stigmatized especially in

women and causes psychological distress.
► Obesity is associated with diabetes
► Obesity is associated with hypertension
and heart disease
► Obesity is associated with cancer
► Obesity is associated with osteoarthritis
and much disability.
The Prevalence of Diabetes in the US
CDC website
Diabetes
► The prevalence of diabetes has tripled since the 1980’s and is increasing
► It is estimated that 8.2% of the US population had Type 2 diabetes in 2010 and it
is predicted that 10.8% will have Type 2 diabetes by 2020
► 0.2% of the population have type 1 diabetes and 3.1% have undiagnosed
diabetes
► 28.4% of the US has pre-diabetes
Diabetes is Expensive
► It is estimated the diabetes costs the US health care system $194 billion in 2010
and will cost an estimated $500 billion in 2020.
► The US will spend approximately $3.4 trillion in the next decade on diabetes-
related care
► The expense of diabetes and those associated obesity-related diseases like cancer,
cardiovascular disease and others are and will stress our health care delivery
system
Obesity Increases Risk of Diabetes
Obesity Increases Disability
Mortality Risk with Staging System
* *
HR for All Cause
HR for All CVD

*
*
Ref Ref
Kuk JL et al. Appl Physiol Nutr Metab. 2011;36:570-576

Association Between EOSS and Mortality Risk in
Aerobics Center Longitudinal Study (n = 29 533)
Kuk JL, et al. Appl. Physiol. Nutr. Metab. 2011;36: 570

Obesity Related Disease Improves with
Weight Loss
Sjostrom L et al. N Engl J Med. 2007;357(8):741-52

Summary
► Obesity can be diagnosed by class and stage

► People in the US are less active and eating more, but multiple causes for obesity exist
► Complications of obesity include diabetes, heart disease, cancer and increased mortality
► Obesity is expensive and straining our health care delivery system
► It is of utmost importance to screen for obesity and intervene in its management
Regulating Energy Balance:

The Pivotal Role of the Central Nervous
System in Appetite Regulation
Focus on 5HT2c Receptors and Other CNS Signaling

Systems Controlling Neuroregulation of Energy Balance
DONNA H. RYAN, MD
Professor and Associate Executive
Director for Clinical Research
Baton Rouge, LA
Weight Regulating Mechanisms and Effect of Anti-
obesity Drugs – Its Complicated!
Endogenous Signaling of Appetite-regulating Hormones, Neuropeptides, and Neurotransmitters, and The Drugs That Target These Pathways
Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics (2010) 87 6, 652–662. doi:10.1038/clpt.2010.57 Slide:Dr. Caroline Apovian
ENERGY
EXPENDITURE
Sedentary
ENERGY Lifestyle
INTAKE
High Energy
Genetic
Dense Foods Susceptibility
(sugar or fat)
(Underlying basisj
Feedback Model
Controller
Afferent
Signals
Controls
Efferent
Fat
Controlled
System
Feedback Model
Controller
Anatomy
Monoamines
Peptides
Cytokines
Afferent
Signals
Controls
Efferent
Fat
Controlled
System
Picture of Frohlich’ s Case of
Hypothlamic Obesity
Location of Hypothalamic
Centers That Affect Feeding
Thalamus
Mamillo-
thalamic
Track
Dorsal
Hyopthalmus
Dorsomedial
Hypo
Lateral Hypo
Surap-optic
nucleus
Ventromedial
Hypo
Ventromedial
Hypothalamic Lateral
La Hypothalamic
Lesions Lesions
Feedback Model
Controller
Anatomy
Monoamines
Peptides
Cytokines
Afferent
Signals
Controls
Efferent
Fat
Controlled
System
Monoamines and Nutrients that
Affect Food Intake
Increase Decrease
► Serotonin
►Anandamide (cannabinoid ► Gamma-amino butyric
agonist) acid (GABA)
► Histamine
► Noradrenergic Agents
Phentermine: A Noradrenergic Drug Reduces
Body Weight
0 0
Continuous Phentermine
Alternate Phentermine & Placebo
4
Placebo
8
Weight loss (kg)

Weight loss (lbs)
5
12
16
20
10
24
28
32
0 4 8 12 16 20 24 28 32 36
Time in Weeks
Munro JF et al BMJ 1968;1:352-4
Serotonin Biology - I
► Serotonin is most concentrated in the

hypothalamus, basal ganglia and brainstem
► 7 groups of 14 serotonin receptors are known
► 5HT-1 - Intronless, G-protein coupled receptor
that inhibits adenylyl cyclase
► 5HT-2
● Contains introns, that are coupled to G-protein
receptors that activate phospholipase C
● 5-HT2C is only in the brain
► 5HT-3 - Ligand-gated ion channel

Serotonin Biology - II
► Activation of 5-HT1A auto-receptor increases

feeding
► Activation of 5-HT1B and 5-HT2C by any agonist 5-
HT agonist will reduce food intake
► 5-HT receptors in PVN specifically decrease fat
intake
► Knock-out of 5-HT2C receptor produces obesity and
convulsions.
► Serotonin reuptake inhibitors and releasers can
precipitate weight loss or weight gain
Serotonin (and Other Agonists) in
PVN Reduce Food Intake
14
2-Hr Food Intake (kcal)
12
10
Saline
8
Serotonin
6
Carbohydrate Fat Protein

Macronutrient Choice
Smith B et al AJP 1999
INDEX Study Completers
1 2 4 6 8 10 12 months
0
Mean Weight Loss (% Initial Weight)
dexfenfluramine n = 248
-3
placebo n = 221
p<0.01
-6
-8
-12
Treatment X Time Interaction To T12 p<0.001 / T6 T12 p<0.01
Guy-Grand et al INDEX study Lancet 1988

Serotonin Interacts with Melanocortin Pathways
Regulating Energy Homeostasis
► Anorectic serotonin (5-HT) drugs activate pro-

opiomelanocortin (POMC) neurons in the arcuate
nucleus of the hypothalamus.
► A serotonin 2C receptor is expressed on POMC
neurons and contributes to this effect.
► Hypohagia induced by serotonin (5-HT) is
attenuated by either pharmacological or genetic
blockade of downstream melanocortin 3 and 4
receptors.
Heisler LK, Dowley MA Kishi T. Ann N Y Acad Sci. 2003 Jun;994:169-74.

5-HT2CRs Expressed by Pro-opiomelanocortin Neurons
Regulate Insulin Sensitivity in Liver
► Mice lacking 5-HT 2C receptors have hepatic insulin

resistance
• Which is normalized by re-expression of 5-HT(2C)
receptors only in pro-opiomelanocortin (POMC)
neurons
► Evidence that 5-HT2CRs expressed by POMC neurons are
physiologically important in regulating hepatic glucose
production and insulin sensitivity
► Moreover, this 5-HT2CR-melanocortin circuit is sufficient to
mediate the anti-diabetic effects of 5-HT2CR agonists.
Xu Y, et al Nat Neurosci. 2010 Dec;13(12):1457-9. Epub 2010 Oct 31

Serotonin 2c Receptor and Diabetes
POMC –
Serotonin 5-HT2c
Hypothalamus
Insulin resistance
Intestines, Fat cells and the rest

Liver of the body sending up signals
to stop eating
Serotonin and Melancortin Receptors
We conclude that serotonin (5-HT) drugs

require functional 5-HT2C receptors in the
POMC that modulate melanocortin pathways to
exert their effects on food intake.
In animals without serotonin receptors,

replacement specifically in the POMC neurons
restores suppression of insulin by CNS serotonin
Heisler LK, Dowley MA Kishi T. Ann N Y Acad Sci. 2003 Jun;994:169-74

.
Feedback Model
Controller
Anatomy
Monoamines
Peptides
Cytokines
Afferent
Signals
Controls
Efferent
Fat
Controlled
System
Peptides That Affect Food Intake
Increase Decrease
► Agouti-related peptide ► α-MSH

► Dynorphin ► Corticotrophin-releasing
► Ghrelin hormone
► Melanin-concentrating ► Cholecystokinin
hormone ► Cocaine-amphetamine
► Neuropeptide Y regulated transcript
► Orexin A (Hypocretin) ► Glucagon-like peptide-1
► RF-2 peptides (arginine ► Leptin
phenylalanine amide-2) ► Amylin
► Galanin-like-peptide ► Bombesin/GRP
► Obestatin (part of ghrelin)
► Nesfatin-1 (NEFA-NUCB2)
Peptides That Affect Food Intake
Increase Decrease
► Agouti-related peptide ► α-MSH

► Dynorphin ► Corticotrophin-releasing
► Ghrelin hormone
► Melanin-concentrating ► Cholecystokinin
hormone ► Cocaine-amphetamine
► Neuropeptide Y regulated transcript
► Orexin A (Hypocretin) ► Glucagon-like peptide-1
► RF-2 peptides (arginine ► Leptin
phenylalanine amide-2) ► Amylin
► Galanin-like-peptide ► Bombesin/GRP
► Obestatin (part of ghrelin)
► Nesfatin-1 (NEFA-NUCB2)
Leptin the Ultimate Messenger
of Fat Stores
POMC –
Serotonin 5-HT2c Weight
Loss
Hypothalamus
Leptin
Intestines, Liver, Pancreas and the rest

Fat Cells of the body sending up signals to stop
eating
Model of the Arcuate Nucleus
Model showing the afferent

signals from the periphery
that modulate the activity
of hypothalamic neurons in
a reciprocal way to increase
or decrease food intake
Badman, Science 2005

Feedback Model
Controller
Anatomy
Monoamines
Peptides
Cytokines
Afferent
Signals
Controls
Efferent
Fat
Controlled
System
Obesity Is Associated with
Inflammatory Hypothalamic Injury
“….Consumption of a High Fat Diet rapidly

induces neuronal injury in a brain area
critical for energy homeostasis.“
Thaler, J et al, J Clin Invest. 2012 Jan 3;122(1):153-62.

Hypothalamic Inflammatory Markers
Increase on High Fat Diet
Data are after 3 days

of eating a high fat diet
2.0
mRNA (fold increase)
2.0
1.5
1.0
0.5
Il1-b Il-6 Tnf-α Socs3 Nfkb IkBkb IkBkθ
Inflammatory Markers
Thaler JP et al J Clin Invest 2012;122:153-162
Obesity Is Associated with
Inflammatory Hypothalamic Injury
“….Consumption of a HFD rapidly induces neuronal injury in a

brain area critical for energy homeostasis.“
“In human beings there is MRI evidence for gliosis in the

hypothalamus of obese humans.”
“Collectively, this work identifies a potential link between

obesity and hypothalamic injury in humans as well as animal
models.”
Thaler, J et al, J Clin Invest. 2012 Jan 3;122(1):153-62.

Does This Explain How Something Environmental Turns
Into Something “ Physical?”
► High fat diets and inflammation
● Evidence of apoptosis and glial ensheathment of ARC neurons in
animals rendered obese by chronic HFD feeding.
► Moreover, these responses were detected specifically in ARC
POMC cells
► 25% reduction in the number of hypothalamic POMC neurons
● Mice chronically fed a HFD.
► POMC cells play an essential role to protect against obesity
► Loss of these cells is sufficient in and of itself to cause excess
weight gain in mice
Fattening Foods Cause Dropout of POMC Neurons and Glial

Ensheathment of ARC Neurons. Does That Explain Why It’s
So Hard To Lose Weight?
Leptin Resistance and Cytokines
► “Taking all of these phenomena into account, we

think that it is possible that overconsumption of
nutrients could be a reason for development of
leptin resistance”
► “This line of thinking favors the fact that increased
adiposity and consequent hyperleptinemia
decreases the leptin action and creates the leptin
resistance”
Ergin A, Cell Metabolism 2008;12:2004

Hypothetical “ Feed-forward,” Positive Feedback
Mechanism Drives Weight Up
• “Brain can’t tell how

• High Fat Hypothalamic injury much fat is stored”
• High Carb POMC neuron dropout • Increases fat mass to
Food Leptin resistance restore equilibrium
• Reduced sense of
satiety and
• Increased • Increased food intake cravings
• Hypothalamic • Weight gain • Metabolic effects
injury
• Increased leptin
resistance
Wang J, Diabetes, 2001; DiMarzo V pers

© 2012 Louis J. Aronne, MD comm
Ozcan L et al Cell Metabolism; 2009
What is Causing the Epidemic of Obesity and
Why Is It So Hard to Lose Weight?
Afferent Signals Central Signals
Efferent
Stimulate Inhibit
NPY Orexin-A α-MSH CART
AGRP Dynorphin CRH/UCN NE
galanin Cannabinoids GLP-I 5-HT
Ghrelin
GLP-1 Autonomic
CCK External Factors Nervous
Vagus Food Availability, System
Palatability
Meal Size Food
Gut and Liver Intake
Amylin
Insulin Pancreas Energy
Energy
Balance
Expenditure
Adipose Tissue and
Leptin
Adipose
Stores
Adrenal Steroids Adrenal Cortex
Adiponectin
© 2007 LJ Aronne MD. Adapted from Campfield LA et al. Science. 1998;280:1383-1387; Porte D et al.
Diabetologia. 1998;41:863-881.
Weight Regulating Mechanisms and Effect of Anti-
obesity Drugs – It’s Complicated!
Endogenous Signaling of Appetite-regulating Hormones, Neuropeptides, and Neurotransmitters, and The Drugs That Target These Pathways
Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics (2010) 87 6, 652–662. doi:10.1038/clpt.2010.57 Slide:Dr. Caroline Apovian
Treatment Gap in the
Management of Obesity
Physicians Need Effective Pharmacotherapies That Will Reduce

Weight Significantly and Reduce Weight-related Comorbidities
Current
Pharmacotherapy
Too risky for many people
Lap Band Gastric Bypass
Treatment
Gap
0% 5% 10% 15% 20% 25% 30% 35%
What will fill the gap ?

New meds, combos, less invasive surgery
New Frontiers and Treatment

Paradigms for Pharmacologic
Management of Obesity
Focus on Safety and Efficacy of Agents Affecting

CNS Signaling Systems and Appetite Regulation
Program Chairman
Professor
Baton Rouge, LA
Where Have We Been?
Where Are We Going?
► Obesity: A physiologically controlled chronic

disease. Medications work when taken.
► Safety and benefit issues with obesity
► The evolution of chronic disease medications
► Drugs recently approved
► Drugs in late development
► Obesity drugs in the future
Fenfluramine
1-Year Rx & 1-Year Follow-up
30
25
20
Pounds
15
10
0
o. o. o. o.
o. o. o. o.
o. o. o. o. o.
m m m m m m m m m m m m m
0 2 4 6 8 10 12 14 16 18 20 22 24
Relationship Between Mortality and BMI
2.5
Men
Women
Mortality Ratio
2.0
1.5
1.0
Very Very
Low Moderate High
Low High
0
20 25 30 35 40
Body Mass Index, kg/m2
Data from Lew EA: Mortality and weight: insured lives and the American
Cancer Society studies. Ann Intern Med 103:1024-1029, 1985.
Chronic Disease Drug Development
Hypertension Obesity
► Surgery – sympathectomy ► Surgery – gastric bypass

► Diuretics – salt in urine ► Orlistat – calories in stool
► CNS drugs – side effects eg. ► CNS drugs – side effects
reserpine and depression eg. amphetamine and
► Combinations to lower side addiction
effects and increase efficacy
eg. Serapes
► Combinations to lower
side effects and increase
► Peripherally acting drugs eg.
efficacy eg topiramate-
angiotensin receptor
blockers
phentermine
► Peripherally acting drugs
(in development)
Obesity Pharmacotherapy
A Bad Safety Record
► 1893: Thyroid hormone -> hyperthyroidism

► 1933: Dinitrophenol -> cataracts/neuropathy
► 1937: Amphetamine -> addiction
► 1967: Rainbow pills (digitalis & diuretics) CV sx
► 1997: Fenfluramine -> valvulopathy
► 2000: Phenylpropanolamine – stroke
► 2004: Herbal caffeine & ephedra CV sx
► 2010: Sibutramine -> MI and stroke
Efficacy of Obesity Drugs
Drug Average Weight Loss LOCF

►Phentermine ► 3.6% > placebo
►Orlistat ► 2.75% > placebo
►Lorcaserin ► 3.3% > placebo
►TopiramatePhentermine ► 9% > placebo
►BupropionNaltrexone ► 4.8% > placebo
►Liraglutide ► 5% > placebo
►BupropionZonisamide ► 9% > placebo

Serotonin Receptors
► 5HT2C receptors are in the brain and act on appetite, but have other potential
drug uses like mood and cognition. EC50 39nM
► 5HT2A receptors are in the brain and other organs like the lung and have
potential psychiatric and sleep uses. EC50 553nM
► 5HT2B receptors are in the brain and other organs like the heart valves. They
have a role in the serotonin syndrome. EC50 2380nM
Lorcaserin
► Brand name: Belviq

► Approved in 2012 (10 mg BID) for long-term weight
management
► Mechanism: Selective 5-HT2C receptor agonist–increases
satiety
► Most common AEs: Headache, nausea, dizziness, fatigue,
dry mouth, constipation
► Notes
● Discontinue if 5% weight loss is not achieved by week 12
● Discontinue for evaluation if signs or symptoms of valvular
heart disease
● DEA Schedule CIV
● Pregnancy category X
Bays HE. Expert Rev Cardiovasc Ther. 2009;7:1429-1445; Belviq [prescribing information]. Woodcliff Lake, NJ:
Eisai; Inc. 2012.
Lorcaserin
Phase III Development Program
► Behavioral Modification and Lorcaserin for

Overweight and Obesity Management Trial
(BLOOM)
► Behavioral Modification and Lorcaserin Second
Study for Obesity Management (BLOSSOM); and
Behavioral Modification
► Lorcaserin for Overweight and Obesity
Management in Diabetes Mellitus (BLOOM-DM).
Bays HE. Lorcaserin and adiposopathy: 5-HT2c agonism as a treatment for ‘sick fat’ and metabolic disease. Expert Rev.
Cardiovasc. Ther. 7(11), 1429–1445 (2009)
BLOOM Study
Body Weight Over Years 1 and 2
102
Year 1 Year 2
100
Body Weight (kg)
98
96
94
92
Placebo in year 1 and 2 (n = 684)
90 Lorcaserin in year 1, placebo in year 2 (n = 275)
Lorcaserin in year 1 and 2 (n = 564)
0
0 8 16 24 32 40 48 56 64 72 80 88 96 104
Study Week
BLOOM = Behavioral Modification and Lorcaserin for Obesity.

Smith SR, et al. N Engl J Med. 2010;363:245-256.
BLOOM Study
Key Secondary End Points
End Point Lorcaserin Placebo P Value

Waist circumference (cm) -6.8 -3.9 <.001
Blood pressure (mm Hg)
Systolic -1.4 -0.8 .04
Diastolic -1.1 -0.6 .01
Total cholesterol (% Δ) -0.90 0.57 .001
Triglycerides (% Δ) -6.15 -0.14 <.001
Safety
HR (beats/min) -2.0 -1.6 .0499
PASP (mm Hg) -0.92 -0.23 0.14
Beck depression II score -1.1 -0.9 0.26
HR = heart rate; PASP = pulmonary artery systolic pressure.

Echocardiographic Monitoring and Endpoints in
Phase 3 Studies
Pulmonary
Aortic
valve  FDA defines significant
valve
valvular regurgitation* as:
Mitral MILD or greater aortic

valve
regurgitation and / or
MODERATE or greater mitral
Tricuspid
valve regurgitation
Regurgitant Scores:
• Absent
• Trace
• Mild
• Moderate
• Severe
*Morbidity and Mortality Weekly Report 46(45): 1; November 1997

Summary of Echocardiographic
Safety Monitoring
► More than 20,000 echocardiographs

► More than 7,500 patients
► Lorcaserin did not increase the risk of valvulopathy
above the pre-specified margin relative to placebo
► Lorcaserin did not meaningfully affect regurgitant
scores at any heart valve
► FDA defined valvulopathy relative risk: 1.16 (95%
confidence interval (0.81, 1.67, NS)
Lorcaserin: No Increase in
Rate of Valvulopathy
9
Patients (%)
19 14
17 5 13
28 34
21 25
Week

BLOOM-DM
Change in Glycemic Parameters
HbA1C, -0.5% Fasting Plasma Glucose

Change From Baseline (%)
Change From Baseline

(mg/dL)
*
†
*
* * * *
Study Week Study Week
Lorcaserin 10 mg twice a day
*P <.001; †P <.05; least square mean change ± standard error of the mean.
HbA1C = glycosylated hemoglobin.
O’Neil PM, et al. Obesity. 2012;20:1426-1436.
Obesity / Lipids
Investigational Anti-
LDL-C TG HDL-C
Obesity Agent
PHEN/TPM CR   
No significant
Lorcaserin   change
Bupropion SR/ No significant

Naltrexone SR change  
Bays HE. Specialty Corner: Investigational Anti-obesity Agents to Treat Adiposopathy and "Sick Fat.” Lipid Spin.
Pages 22-23. 2011
BLOSSOM
Body Weight Change from Baseline to Week 52
Fidler, et al. J Clin Endocrinol Metab, October 2011, 96(10):3067–3077

Phentermine and Fefluramine
Phen - Fen
Weintraub M et al. Clin Pharmacol Ther. 51(5):586-94, 1992.

Phentermine/Topiramate
► Dose (am): 3.75/23mg 2 weeks then 7.5/46mg

► If weight loss <3% in 12 weeks, stop or 15/92mg
► Stop (taper) 15/92mg after 12 weeks if <5% loss
► Safety: fetal cleft palate - pregnancy test q mo.
Elevated heart rate, suicidal ideation, glaucoma,
sleep disorders, cognition impaired, metabolic
acidosis. DEA Class IV and REMS program
► Adverse events >5% and 1.5 times greater than
placebo: paresthesia, dizziness, dysgeusia,
insomnia, constipation and dry mouth.
Phentermine/Topiramate Phase III Trial
3.75/23 mg & 15/92 mg
Allison DB et al. Obesity. 20(2):330-42, 2012

Phentermine/Topiramate Phase III Trial
7.5/46 mg & 15/92 mg
Gadde KM et al. Lancet. 2011;377(9774):1314-52

Naltrexone/Bupropion
► Dose: 3 week escalation to 16/180mg SR bid

► Improved HDL, triglycerides, hsCRP, HOMA-IR
& QOL. HgbA1c dropped 0.5% in diabetics
► Adverse events >5% and >1.5 times control:
Nausea, headache, constipation, dizziness,
vomiting, insomnia, dry mouth & hot flushes
► No DEA designation yet, reduces cravings
► Doing cardiovascular safety trial (BP & pulse)
Bupropion 360 & Naltrexone 32 mg
Placebo (N=511) NB16 (N=471) NB32 (N=471) Placebo NB16 NB32
Completers (N=290) Completers (N=284) Completers (N=296)
ITT-LOCF Observed Completers

0 0
Change from baseline (%)
Change from baseline (%)

-1.3%
-2 -2 -1.8%
-4 -4
-5.0%
-6 -6.1%† -6
-6.7%
-8 -8 -8.1%
-10 -10
0 8 16 24 32 40 48 56 0 8 16 24 32 40 48 56
Week Week
Placebo-subtracted weight loss Placebo-subtracted weight loss

Week 56 Completers
NB16: -3.7% NB16: -4.9%
NB32: -4.8% NB32: -6.2%
P<0.001 for NB16 and NB32 vs. Placebo at all time points
Greenway FL et al. Lancet. 376(9741):595-605, 2010

Liraglutide 3 mg/d in Obese Subjects
Astrup A et al. Lancet 374(9701):1606-16, 2009

Empatic™ (Zonisamide 360 & Bupropion 360 mg)
Weight Loss at 1 Year of Treatment
Placebo (a) Z120/B280 Z120/B360 Z240/B280 Z240/B360 Z360/B280 Z360/B360

(N=72) (N=27) (N=36) (N=36) (N=26) (N=32) (N=39)
0%
-1%
-1.2%
-2%
-3%
-4%
-5%
Mean Weight Loss
-6%
-7%
-8%
-9%
-10%
-11%
-10.9%
-12% -11.6%
-12.1%
-13% -12.5%
-12.9%
-14%
-15%
-14.9%
-16%
(a) Placebo weight loss through 24 weeks as noted previously

Belornib - Body Weight in Mice
Body weights during the course of 1 mg/kg/day fumagillin (ZGN-201) treatment
ERK Cascade And Regulation Of Metabolism
Current Mechanistic Model
HYPERINSULINEMIA
GH, PDGF, GIP, Cell Stress
MetAP2i
Cellular Signal REDUCED ERK1/2 TONE
Transcription
Factor SREBP (inactive) ROR (active)
Pathway Reduced triglyceride Increased FGF21 and

Effect synthesis fatty acid oxidation,
Reduced inflammation
Kotzka et al., Atherosclerosis 213 (2010) 156–65
Delerive et al., EMBO Reports 2001; 21:42-8
118
Belornib - Body weight in Humans
► Impact of 2-18 ug/kg/dose ZGN-433 treatment on body weight in obese women
MetAP2 inhibitor (ZGN-433) treatment induces loss of body weight in obese women.
Body weights were obtained prior to each treatment and plotted as percent weight change from
baseline during treatment with ZGN-433 for 4 weeks and during 10 days of wash-out. Values
are medians ± SEM (n=6-8) for the per protocol population. *** p<0.001 by 2-way ANOVA
and Bonferroni post-test.
EOSS Predicts Mortality in NHANES III

Summary
► Obesity is a chronic physiologically controlled disease that requires chronic treatment

► We have two new CNS acting drugs for obesity lorcaserin and phentermine/topiramate
► There are 3 drugs in late stage development: naltrexone/bupropion, liraglutide, and
zonisamide/bupropion
► Peripherally acting drugs may limit serious side effects, but only orlistat now is approved
Real World Challenges in

Obesity Management
Case Study-Based Learning Workshops and Clinical
Simulations in Obesity Management
Program Chairman
Professor
Baton Rouge, LA
Case Study 1
 ER, a 46-year-old woman, initially presents with high blood
pressure, which has been well controlled with a diuretic agent.
 Since her last visit 6 months ago, she has been experiencing
some heartburn, self-treated with over-the-counter H2-blockers,
and more aching in her weight-bearing joints.
 On exam, her height is 66 inches and body weight is 190

pounds, up 5 pounds from her last visit. Blood pressure is
134/90, up several points from her last visit as well. The rest of
the exam is unchanged.
 Her previous lab tests were within normal limits. Current test
results indicate a fasting glucose of 118 mg/dL, total
triglycerides of 255 mg/dL, and high-density lipoprotein (HDL
cholesterol) of 42 mg/dL. All other tests are normal.
Case Study 1
 With a height of 66 inches and weight of 190 pounds, ER’s BMI
is 31. This places her in Class I (mild) obesity.
 Her waist circumference is 36 inches. This, in addition to her

triglycerides of 225 mg/dL, fasting glucose of 118 mg/dL, HDL
cholesterol of 42 mg/dL, and blood pressure of 134/90, shows
that she has the metabolic syndrome. This places her at
increased risk of cardiovascular disease.
 In reviewing ER’s history, you identify five obesity-related

conditions:
 Hypertension
 Gastroesophageal reflux disease (GERD)
 Impaired glucose tolerance (possible diabetes)
 Hypertriglyceridemia and low HDL-C levels
 Arthralgia
Case Study 1 - Question 1
 You decide to order additional tests to evaluate ER’s
hypertension and diabetes.
 Based on the NHLBI algorithm, treatment for ER’s

obesity is indicated.
 At this point you would:
1. Recommend diet and lifestyle changes

2. Initiate orlistat
3. Initiate lorcaserin
4. Initiate phentermine
5. Initiate phentermine HCl/topiramate CR
Please Enter Your Response On Your Keypad
 In this case, diet and lifestyle changes were
recommended, with an assessment after 90 days.
 The patient returned with an additional 2 lb. weight

gain and reported difficulty in maintaining diet.

1. Modify diet and lifestyle recommendations and reassess in
90 days
2. Initiate orlistat
3. Initiate lorcaserin
4. Initiate phentermine
5. Initiate phentermine HCl/topiramate CR

 90 days later, she is tolerating the weight
management drug well, has experienced a 5% weight
loss, and improvement in metabolic parameters. She
reports increased energy and improved self-esteem.
1. Cease pharmacotherapy and recommend diet and lifestyle

changes
2. Cease pharmacotherapy, recommend diet and lifestyle
changes, and revisit in 90 days
3. Maintain current pharmacotherapy
4. Switch to alternative pharmacotherapy
 90 days later, she is not tolerating the weight
management drug well, has experienced a 5% weight
loss, and improvement in metabolic parameters. She
reports increased energy and improved self-esteem.
1. Cease pharmacotherapy and recommend diet and lifestyle

changes
2. Cease pharmacotherapy, recommend diet and lifestyle
changes, and revisit in 90 days
3. Maintain current pharmacotherapy
4. Switch to alternative pharmacotherapy
Case Study 2
42-year-old man with BMI 37
•Weight 242 lbs., up 5 lbs. from 6 months earlier
•Gout well-controlled on allopurinol
•Hyperlipidemia (on low-dose simvastatin); bilateral knee arthritis
Examination
• Central obesity with waist circumference 44 in.
• BP 132/82
Laboratory studies
• Fasting glucose 90
• Fasting triglycerides 260
• Cholesterol 220; LDL cholesterol 146; HDL cholesterol 38
• Other tests normal
Case Study 2
Weight and lifestyle history
• Mildly heavy as a child
• “Grew out of it” during adolescence; participated in
competitive sports in high school and college
• Weight stable at ~185 lbs. (BMI 28.3) until 12 years ago
• Slowly progressive 55 lb. weight gain over last 10 years
• Works as salesman with hectic lifestyle; irregular meals;
frequent fast foods and snacking
• No previous serious weight loss attempts; feels healthy
• Has exercised at gym 4x/week over the past year with only
4 lb. weight loss
You increase the dose of simvastatin.

42 M
What would you do to treat the obesity? BMI 37
Central distribution
1. Recommend a healthier and more regular diet Pre-DM
Dyslipidemia
2. Encourage a more vigorous exercise program GERD
Gout
3. Refer him to a psychologist for behavior OA
modification
Childhood onset
Steady adult gain
4. Initiate orlistat therapy
Irregular eater
5. Initiate lorcaserin therapy Fast food diet
Regular exerciser
Hectic lifestyle
Case Study 2
Clinical progress
• He listens to your dietary advice and stops snacking
• His hectic lifestyle continues, but he eats more
meals at home and is able to change from fast food
to family style restaurants when traveling
• Continues to exercise regularly
• Lost 4 lbs. (to 238 lbs.) in the first month but none
since, despite maintaining his new lifestyle
• At follow-up 3 months later, his weight is 239 lbs.,
BP 128/84 and LDL and total cholesterol in the
normal range
Case Study 2 – Question 2
What would you do now?
1. Continue to encourage a healthy diet
2. Refer to dietitian for nutritional management
3. Refer to a stress management program
4. Initiate phentermine therapy
5. Initiate lorcaserin therapy

Case Study 2
Clinical progress
• He sees a dietitian who recommends a specific dietary
regimen, which he follows reasonably well
• Over the ensuing 3 months, he loses 12 lbs.
• At his annual visit 9 months after that, however, he
has regained 10 of the 12 lbs. and weighs 237 lbs.
(BMI 36.2)
• His cholesterol levels and BP remain normal
• His fasting glucose is 114, and his triglyceride level is
222, and his HbA1c is 6.6%
1. Continue to encourage a healthy diet
2. Refer back to the dietitian for additional counseling
3. Refer to a stress management program
4. Initiate phentermine therapy
5. Initiate lorcaserin therapy

Case Study 2
Clinical progress
• You begin phentermine at 15 mg/day, monitoring BP and pulse
carefully
• He reports dry mouth that resolves after about 3 weeks; he
otherwise tolerates the medication well, without tachycardia,
hypertension or subjective adverse effects
• At 30 days, he has lost 5 lbs. (2.1% of pretreatment weight)
• At 3 months, he weighs 223 lbs. (BMI 34.1), having lost 14 lbs.
(5.9%) on phentermine
• He continues the recommended dietary changes
• Two months later (on phentermine for 5 months), he has lost 1
additional lb. and weighs 222 lbs. (BMI 33.9)
• Total weight loss 20 lbs. since first visit; total weight loss on
phentermine 15 lbs. (6.3%)
1. Continue the phentermine at 15 mg/day and re-

emphasize the recommended diet and lifestyle changes
2. Stop the phentermine and follow his clinical progress
3. Stop the phentermine and start orlistat at 120 mg

tid
4. Increase the phentermine to 30 mg/day
5. Recommend consultation for bariatric surgery

Case Study 2
Clinical progress
• He tolerates the increased dose of phentermine well
with only transient dry mouth
• At 30 days, he has lost 2 additional lbs. (0.8% of
pretreatment weight)
• At 3 months, he weighs 221 lbs. (BMI 33.8), having
lost 16 lbs. (5.9%) on phentermine overall
1. Continue the phentermine at 30 mg/day and refer back to

the dietitian
2. Stop the phentermine and follow his clinical progress
3. Stop the phentermine and start orlistat at 120 mg tid
4. Add topiramate by substituting the low-dose combination of

phentermine (3.75 mg/day) and topiramate (23 mg/day) for the
phentermine alone

Case Study 2
Clinical progress
• He tolerates the low-dose phentermine-topiramate
combination (“phen-top”) well, without adverse effects
• After 14 days, you increase the phen-top dose to 7.5 mg
phentermine + 46 mg topiramate daily
• In the first 30 days of phen-top therapy, he loses 3 lbs.
to a weight of 218 lbs. (BMI 33.3)
• Over the next 3 months, he loses an additional 8 lbs. to
a weight of 210 lbs. (BMI 32.1)
Case Study 2
Weight loss summary

• Initial weight 242 (BMI 37)
• Diet modification – 5 lb. weight loss over 1 year (2.1%)
• Phentermine – 16 lb. weight loss over 8 months
(6.8%)
• Phentermine-topiramate combination – 11 lb. additional
weight loss over 4 months (4.9%)
• Total medication-induced weight loss – 27 lbs. (11.4%)
• Current weight 210 lbs. (BMI 32.1), down 32 lbs.
(13.2%) overall since initial visit 2 years earlier
1. Continue the phen-top at current dosing
2. Stop the phen-top, re-enforce lifestyle adjustments and

follow his clinical progress
3. Increase the phen-top dosing to 15 mg phentermine + 92

mg topiramate daily (“high dose”)
4. Add lorcaserin at 10 mg bid

Case Study 3
• 51-year-old woman with BMI 43.3

• Weight 252 lbs., height 5’4”
• Well-controlled hypertension, hypothyroidism, Barrett’s
esophagus, osteoarthritis (s/p knee replacement), colonic
polyps, and depression
• Type 2 diabetes on pioglitazone, glimepiride and insulin (long-
and short-acting to total of 65 units/day)
• no eye, neurological or vascular complications
• Sleep apnea well-controlled on CPAP
• Other medications include losartan, hydrochlorthiazide,
omeprazole, levothyroxine, omeprazole, aspirin and sertraline
Case Study 3
Examination
• Benign, protuberant abdomen; no signs of chronic liver disease
• No signs of peripheral neuropathy
• Benign abdomen
Laboratory studies
• Fasting glucose 111
• HbA1c 7.1%
• AST 43, ALT 51, alkaline phosphatase 120
• BUN 32; creatinine 1.2
• TSH 5.64
Case Study 3
• Normal weight as a child; overweight in college and
graduate school (weight 150-175; BMI 26-30)
• Progressive weight gain in adult life; “insatiable” appetite
with frequent cravings and large portions
• Numerous unsupervised, supervised and structured diets
with variable weight loss (up to 30 lbs.); none maintained
• Average weight stable over the past few years; currently at
highest lifetime weight
• Married with grown children; works as financial planner
• Cooks regularly and well, and entertains often
• Exercises three times a week with a physical trainer
You increase the dose of L-thyroxine.

51 F
How would you initiate obesity treatment? BMI 43.3
1. Recommend a meal-replacement program T2DM (55
OSA
2. Substitute citalopram for sertraline Hypothyroidism
GERD / Barrett’s
OA
3. Refer her to a psychologist for cognitive-
Colonic polyps
behavior therapy for the depression Depression
4. Substitute metformin for glimepiride Adult onset

Healthy diet
5. Initiate treatment with a combination of Often hungry
Large portions
phentermine and topiramate
Regular exerciser
Case Study 3
Clinical progress
• You discontinue the sulfonylurea and start metformin at 500
mg bid, monitoring her glucose carefully and adjusting short-
acting insulin as required
• In the next 30 days, she loses 5 lbs. to a weight of 247 lbs.
(BMI 42.4)
• You increase the metformin to 750 mg bid
• At 3 months, she has lost a total of 14 lbs. (5.6%) to 238 lbs.
• She reports a noticeably diminished appetite and cravings
• Insulin requirement falls from 65 to 52 units/day
• 3 months later, her weight is stable at 235 lbs. (BMI 40.3),
down 17 lbs. (6.7%)
What would you do now to treat the obesity?
1. Refer to a commercial weight loss program
2. Substitute bupropion for sertraline
3. Initiate therapy with a combination of phentermine and

topiramate
4. Initiate therapy with lorcaserin
5. Refer for bariatric surgery

Case Study 3
Clinical progress
• Low-dose phen-top (phentermine 3.75 mg +
topiramate 23 mg daily) initiated and well-tolerated
• After 14 days, you increase the phen-top dose to
phentermine 7.5 mg + topiramate 46 mg daily with
no adverse consequences
• In the first 30 days of therapy, she loses 4 lbs. (1.7%)
to 231 lbs. (BMI 39.6)
• At 3 months, she has lost a total of 6 lbs. (2.6%) to
229 lbs.
1. Continue the phen-top at current dosing and add

orlistat at 120 mg tid
2. Stop the phen-top and start phentermine at 15 mg

daily
3. Stop the phen-top and start lorcaserin at 10 mg bid
4. Stop the phen-top and start orlistat at 120 mg tid
5. Stop the phen-top and substitute liraglutide s.c. for

the pioglitazone
Case Study 3.
Clinical progress
• She tolerates the new medication well
• After 30 days, she reports feeling increased hunger
and her weight has increased 3 lbs. to 232 lbs.
• After 60 days, her weight remains at 232 lbs. (BMI
39.8)
• Her diabetes remains well-controlled with a fasting
glucose of 114 and HbA1c of 6.9%
1. Stop all weight loss medications and refer to a dietitian to

reinforce healthy eating habits
2. Stop all weight loss medications and refer to a psychologist

for behavioral therapy
3. Continue the current regimen and restart a combination of

phentermine and topiramate
4. Stop all weight loss medications and institute an 8-week

physician-supervised very low calorie diet (VLCD)
5. Stop all weight loss medications and refer for bariatric surgery
Case Study 3
Clinical progress
• She undergoes uneventful laparoscopic Roux-en-Y gastric
bypass with post-operative weight loss ~50 lbs.
• Her diabetes remains well controlled (HbA1c 6.6%) without
need for insulin, pioglitazone or liraglutide, and on a reduced
dose of metformin (500 mg bid)
• Other comorbidities improved or resolved except for
continued joint pain and reflux symptoms
• One year after surgery, her weight is down 51 lbs. to 181 lbs.
(BMI 31.1), which has been stable for more than 3 months
• She feels much better overall but is a bit disappointed in the
weight loss outcome (which is less than the average 65%
excess weight loss from this operation)
1. Indicate that there is no further therapy beyond surgery and

reinforce the need to follow a healthy lifestyle
2. Refer her to a psychologist to help address her

expectations
3. Encourage her to extend post-operative weight loss with a

low-calorie (calorie restricted) diet
4. Institute pharmacological therapy with phentermine or a

combination of phentermine and topiramate
5. Refer her back to the surgeon for consideration of revising

the surgical procedure
Case Study 3
Clinical progress
• Lorcaserin at 10 mg/day is started and well-tolerated
• Over the next 6 months, she loses an additional 22 lbs.
to a weight of 159 lbs. (BMI 27.3)
• Her comorbidities remain improved, and her diabetes is
in remission off all medications (HbA1c 6.3%)
Case Study 3
Weight loss summary
• Initial weight 252 (BMI 43.3)
• Substitution for weight-promoting drugs – 23 lb. weight loss
over 1 year (2.1%)
• Phentermine-topiramate combination – 16 lb. weight loss over 3
months (2.6%)
• Other pharmacological agents – 3 lb. weight gain over 2 months
(1.3%)
• Total medical weight loss – 20 lbs. (7.9%)
• Gastric bypass – 51 lbs. (22.0%) weight loss over 1 year (58.8%
excess weight loss)
• Lorcaserin after surgery – 15 lbs. over 6 months
• Current weight 159 lbs. (BMI 27.3), down 93 lbs. (36.9%) since
initial visit 3 years earlier
Case Study 4
46-year-old woman with BMI 30.7

•Weight 190 lbs., up 5 lbs. from 6 months earlier
•Hypertension, heartburn, weight-bearing joint pain
Examination
• BP 134/90
Laboratory studies
• Glucose 118; HbA1c 6.4%
• Triglycerides 255 mg/dL, LDL cholesterol 140
• HDL cholesterol 42 mg/dL
Case Study 4

• Normal weight as child
• Progressive weight gain after college exacerbated after
having children in late 20s
• Previously on intermittent diets with up to 20 lb. weight
loss, but invariable weight regain
• Eats mostly home-prepared food
• Little or no snacking, but eats meals irregularly
• Single mother of 2 teenagers, with steady boyfriend
• Works as nursing assistant on evening and night shift
• Walks extensively at work; no structured exercise
What treatment would you initially

recommend for this patient? 46 F
BMI 30.7
1. Broad-based diet and lifestyle counseling
Pre-DM
2. Implementation of moderate structured HTN
exercise regimen Dyslipidemia
GERD
Joint pain
3. Cooking classes
Obesity onset 20s
4. Change jobs Failed diets
Home-cooker
5. Initiate pharmacotherapy for obesity Irregular eater
Walks a lot
Night shift worker
Stressful life
Case Study 4
Clinical progress
• Modest, regular, aerobic exercise program
initiated and maintained
• At follow-up 2 months later, her weight was
down 6 lbs. to 184 lbs. (BMI 29.7)
You recommend that she continue the exercise program.
What else would you recommend now?
1. Laud her success and encourage continuing a healthy lifestyle
2. Refer to exercise trainer to help with exercise
3. Encourage a more regular eating pattern
4. Suggest that she change to day shift
5. Initiate pharmacotherapy for obesity

Case Study 4
Clinical progress
• Continued regular exercise program
• Stopped grazing and began eating on regular schedule
• Change in eating schedule resulted in stabilization of sleep
patterns as well
• At follow-up three months later, her weight was down 8
more lbs. (14 lbs. weight loss total ), to 176 lbs. (BMI 28.4)
• She describes increased energy and improved self-esteem
What would you recommend now?
1. Encourage a healthy diet and reassess HbA1c
2. Refer to dietitian for nutritional management
3. Initiate pharmacotherapy for obesity
4. Recommend bariatric surgical evaluation for type 2 diabetes
5. Refer to plastic surgeon for liposuction

Management of Obisity

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Management of Obisity

Uploaded by

Copyright:

Available Formats

Investigations  Stratification

Front Line Clinical Applications

TIMOTHY CHURCH, MD, MPH, PhD – Program Chairman

PATRICK M. O'NEIL, PhD

Current Challenges and Barriers to

A Year 2014 Status Report for the Primary Care

2.5% 1% 0.05% Lifestyle

Overweight U.S. adults: 67%

Annual U.S. health care expenditures

U.S. consumer expenditures for

Daily deaths from obesity complications > 1,000

Today, more than 1.7 million US adults with BMI>50

 Hides in plain sight

 Did NOT start in the past 30 years

 NOT a problem of eating too much

 NOT a single disorder

 Characterological flaw (willpower, psychology)

 Epidemic from changes in modern environment

 Widely recognized as a disease

 Huge burden of associated illness – a cause of more than

By the laws of physics…

Hunter-Gatherer Hadza and Westerners Have Equal

“ We hypothesize that human daily energy expenditure may be an

Pontzer H, et al., PLoS ONE 2012; 7: e40503

Average adults require approximately 800 kcal/day

Average adults consume 2000-2500 kcal/day

Maintaining weight within 20 lbs. between ages 21 and 65

Maintenance of normal fat stores (and body weight) requires

Sumithran et al. NEJM 2011; 365:1597-1604.

Sumithran et al. NEJM 2011; 365:1597-1604.

Environment Adipose tissue

(3) Stress and distress (4) Drugs

Cortex (1) Altered

*Limited effect of individual action

*Amenable to individual action

Healthy Diet Physical Activity

Healthy Diet Physical Activity

Self-directed Lifestyle Change

Professionally-directed Lifestyle Change

Weight Loss Surgery

Post-surgical Combination Therapies

There is broad variability in the weight loss

 Specific lifestyle interventions

Epidemiology and Clinical Approaches to

What Do Trials, Algorithms, and Clinical Experience

PATRICK M. O'NEIL, PhD

► Obesity is defined an excess of body fat

Padwal R, Sharma AM et al. CMAJ 2011

Stage 1 m cto al moderate Stage 3

Sharma AM & Kushner RF, Int J Obes 2009

► Stage 0: No obesity related risk factors

Sharma AM and Kushner RF. Int J Obes. 2009;33:289-95

Padwal R, Sharma AM et al. CMAJ 2011

Padwal R, Sharma AM et al. CMAJ 2011

► The prevalence of obesity in 1961 was 10%

Church TS et al. Plos One.2011;6(5):e19657

1960 1970 1980 1990 2000 2010

1960 1970 1980 1990 2000 2010

Church TS et al. Plos One.2011;6(5):e19657

et al. Plos One.2011;6(5):e19657

► People are less active and are eating more

► Adenovirus of D group 36 (AD-36) causes obesity in non-human primates

Atkinson RL et al. Int J. Obes. 2005;29(3):281-6

► Obesity is stigmatized especially in