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
MARC-ANDRE CORNIER, MD - Program Chairman
Associate Professor of Medicine
Division of Endocrinology, Metabolism and Diabetes
Anschutz Health and Wellness Center
University of Colorado School of Medicine
Denver, CO
Distinguished Faculty
MARC-ANDRE CORNIER, MD - Program Chairman
Associate Professor of Medicine
Division of Endocrinology, Metabolism and Diabetes
Anschutz Health and Wellness Center
University of Colorado School of Medicine
Denver, CO
REKHA KUMAR, MD, MS
Diabetes, Endocrinology and Metabolism
Weill Cornell Medical College
Assistant Professor of Medicine
New York Presbyterian Hospital
New York, NY
ROBERT J. MALCOLM, MD
Professor, Department of Psychiatry and Behavioral Sciences
Associate Dean for Continuing Medical Education, College of Medicine
Medical University of South Carolina
Charleston, SC
Investigations  Stratification
Front Line Clinical Applications
Current Challenges and Barriers to
Optimizing Management of Obesity
A Year 2014 Status Report for the Primary Care
Physician and Clinical Subspecialist
MARC-ANDRE CORNIER, MD - Program Chairman
Associate Professor of Medicine
Division of Endocrinology, Metabolism and Diabetes
Anschutz Health and Wellness Center
University of Colorado School of Medicine
Denver, CO
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
Psychological
65+
Long-term Control of Obesity – 2013
1% =
750,000
U.S. adults
Obesity is Counterintuitive
 Hides in plain sight
• Most obesity NOT recognized by physicians or the
public
 NOT mainly in America
 NOT simply a problem of eating too much
 NOT a single disorder – very heterogeneous
• 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
 Genetic Predisposition (physiology) in the wrong 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
 Average adults consume 2000-2500 kcal/day
• Average adults therefore consume 2-3 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.
Obesity: A Failure of Weight Regulation
Cortex
Genetics
HT
GI Tract
Food intake
Energy expenditure
Nutrient handling
Leptin
Environment
•
•
•
•
•
Altered food supply
Reduced physical activity
Stress
Drugs
Others?
Adipose tissue
Barriers, Challenges and Opportunities
to Obesity Management
 Our biology

Favors fat storage

Can this be manipulated?
 Environment

Macroenvironment – more difficult to change

Microenvironment – can be changed by the individual?
 Health Care System
 Lack of “buy in” from providers, patients and insurers
 Others?
Investigations  Stratification
Front Line Clinical Applications
Epidemiology and Clinical Approaches to
Obesity Management
What Do Trials, Algorithms, and Clinical Experience
Teach Us About Sequencing Treatment Approaches
for Obesity?
REKHA KUMAR, MD, MS
Diabetes, Endocrinology and Metabolism
Weill Cornell Medical College
Assistant Professor of Medicine
New York Presbyterian Hospital
New York, NY
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
Mortality Ratio
2.5
2.0
Men
Women
1.5
1.0
Very
Low
0
20
Low
25
Moderate
30
High
35
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.
Very
High
40
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
moderate
Stage 3
moderate
Stage 0
Stage 4
Obesity
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
Padwal R, Sharma AM et al. CMAJ 2011
EOSS Distribution Across BMI Categories
NHANES III (1988-1994)
Overweight
23 million
10 million
Class
III
50 million
6 million
Padwal R, Sharma AM et al. CMAJ 2011
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
Occupation Related Daily
Energy Expenditure (calories)
Mean Occupation
Related METs
Fall in Energy Expenditure at Work
1960
1970
1980
1990
2000
2010
1990
2000
2010
Year
1960
1970
1980
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 CVD
HR for All Cause
*
Ref
Kuk JL et al. Appl Physiol Nutr Metab. 2011;36:570-576
Ref
*
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
Investigations  Stratification
Front Line Clinical Applications
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
ROBERT J. MALCOLM, MD
Professor, Department of Psychiatry and Behavioral Sciences
Associate Dean for Continuing Medical Education, College of Medicine
Medical University of South Carolina
Charleston, SC
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
Lifestyle
ENERGY
INTAKE
High Energy
Dense Foods
Genetic &
Biological Susceptibilities
(sugar or fat)
(Underlying basis)
Feedback Model
Signals
Fat
Controlled
System
Efferent
Controls
Afferent
Controller
Feedback Model
Controller
Signals
Fat
Controlled
System
Efferent
Controls
Afferent
Anatomy
Monoamines
Peptides
Cytokines
Picture of Frohlich’s Case of
Hypothlamic Obesity
Location of Hypothalamic
Centers That Affect Feeding
Thalamus
Mamillothalamic
Track
Dorsal
Hyopthalmus
Dorsomedial
Hypo
Lateral Hypo
Surap-optic
nucleus
Ventromedial
Hypo
Ventromedial
Hypothalamic
Lesions
Lateral
La Hypothalamic
Lesions
Feedback Model
Controller
Signals
Fat
Controlled
System
Efferent
Controls
Afferent
Anatomy
Monoamines
Peptides
Cytokines
Monoamines, Peptides, Amino Acids
& Drugs Affecting Food Intake
Increase
Decrease
►
►
►
►
►
Anandamide (cannabinoid
agonist)
Serotonin (5HT-1a auto)
Serotonin Pump Inhibitors
Anti-histamines
►
►
►
►
Serotonin (5 HT-2c)
Gamma-amino butyric
acid (GABA)
Histamine
Noradrenergic Agents
Cannabinoid Antagonists
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 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
2-Hr Food Intake (kcal)
14
12
10
Saline
8
Serotonin
6
4
2
0
Carbohydrate
Fat
Macronutrient Choice
Smith B et al AJP 1999
Protein
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-HT2C Rs expressed by POMC neurons
are physiologically important in regulating hepatic
glucose production and insulin sensitivity
►
Moreover, this 5-HT2C R-melanocortin circuit is
sufficient to mediate the anti-diabetic effects of 5HT2CR 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
Liver
Intestines, Fat cells and the rest
of the body sending up signals
to stop eating
Serotonin Interacts with Melanocortin
Pathways Regulating Energy Homeostasis
► Anorectic serotonin (5-HT) drugs activate proopiomelanocortin (POMC) neurons in the arcuate
nucleus of the hypothalamus.
► A serotonin 2C receptor is expressed on POMC
neurons and contributes to this effect.
► Hypophagia 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.
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;1994:169-74
.
INDEX Study Completers
1
2
4
6
8
10
12
Mean Weight Loss (% Initial Weight)
0
dexfenfluramine
-3
placebo
n = 248
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
months
Phentermine: A Noradrenergic Drug
Reduces Body Weight
8
5
12
16
20
10
24
28
32
0
4
8
12
16
20
24
Time in Weeks
Munro JF et al BMJ 1968;1:352-4
28
32
36
Weight loss (kg)
4
Weight loss (lbs)
0
Continuous Phentermine
Alternate Phentermine & Placebo
Placebo
0
Feedback Model
Controller
Signals
Fat
Controlled
System
Efferent
Controls
Afferent
Anatomy
Monoamines
Peptides
Cytokines
Peptides That Affect Food Intake
Increase
►
►
►
►
►
►
►
►
Agouti-related peptide
Dynorphin
Ghrelin
Melanin-concentrating
hormone
Neuropeptide Y
Orexin A (Hypocretin)
RF-2 peptides (arginine
phenylalanine amide-2)
Galanin-like-peptide
Decrease
►
►
►
►
►
►
►
►
►
►
α-MSH
Corticotrophin-releasing
hormone
Cholecystokinin
Cocaine-amphetamine
regulated transcript
Glucagon-like peptide-1
Leptin
Amylin
Bombesin/GRP
Obestatin (part of ghrelin)
Nesfatin-1 (NEFA-NUCB2)
Peptides That Affect Food Intake
Increase
►
►
►
►
►
►
►
►
Agouti-related peptide
Dynorphin
Ghrelin
Melanin-concentrating
hormone
Neuropeptide Y
Orexin A (Hypocretin)
RF-2 peptides (arginine
phenylalanine amide-2)
Galanin-like-peptide
Decrease
►
►
►
►
►
►
►
►
►
►
α-MSH
Corticotrophin-releasing
hormone
Cholecystokinin
Cocaine-amphetamine
regulated transcript
Glucagon-like peptide-1
Leptin
Amylin
Bombesin/GRP
Obestatin (part of ghrelin)
Nesfatin-1 (NEFA-NUCB2)
Leptin the Ultimate Messenger
of Fat Stores
POMC –
Serotonin 5-HT2c
Hypothalamus
Leptin
Fat Cells
Intestines, Liver, Pancreas and the rest
of the body sending up signals to stop
eating
Weight
Loss
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
Signals
Fat
Controlled
System
Efferent
Controls
Afferent
Anatomy
Monoamines
Peptides
Cytokines
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
mRNA (fold increase)
Data are after 3 days
of eating a high fat diet
2.0
2.0
1.5
1.0
0.5
Il1-b
Il-6
Tnf-α
Socs3
Nfkb
Inflammatory Markers
Thaler JP et al J Clin Invest 2012;122:153-162
IkBkb
IkBkθ
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.
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
►
Does This Explain How Something
Environmental Turns Into Something
“Physical?”
High fat diets and inflammation
●
►
►
Moreover, these responses were detected specifically in ARC
POMC cells
25% reduction in the number of hypothalamic POMC neurons
●
►
►
Evidence of apoptosis and glial ensheathment of ARC neurons in
animals rendered obese by chronic HFD feeding.
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?
Hypothetical “Feed-forward,” Positive
Feedback Mechanism Drives Weight Up
• High Fat
• High Carb
Food
• Increased
• Hypothalamic
injury
• Increased leptin
resistance
© 2012 Louis J. Aronne, MD
Hypothalamic injury
POMC neuron dropout
Leptin resistance
•
•
• “Brain can’t tell how
much fat is stored”
• Increases fat mass to
restore equilibrium
Increased food intake
Weight gain
• Reduced sense of
satiety and
cravings
• Metabolic effects
Wang J, Diabetes, 2001; DiMarzo V pers 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
Stimulate
NPY
Orexin-A
α-MSH
AGRP
Dynorphin
CRH/UCN
galanin Cannabinoids GLP-I
Ghrelin
GLP-1
CCK
Vagus
Amylin
Insulin
External Factors
Food Availability,
Palatability
Gut and Liver
Pancreas
Leptin
Adipose Tissue
Adrenal Steroids
Adrenal Cortex
Efferent
Inhibit
CART
NE
5-HT
Autonomic
Nervous
System
Meal Size
Energy
Balance
and
Adipose
Stores
Food
Intake
Energy
Expenditure
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%
What will fill the gap ?
New meds, combos, less invasive surgery
30%
35%
Investigations  Stratification
Front Line Clinical Applications
New Frontiers and Treatment
Paradigms for Pharmacologic
Management of Obesity
Focus on Safety and Efficacy of Agents Affecting
CNS Signaling Systems and Appetite Regulation
MARC-ANDRE CORNIER, MD - Program Chairman
Associate Professor of Medicine
Division of Endocrinology, Metabolism and Diabetes
Anschutz Health and Wellness Center
University of Colorado School of Medicine
Denver, CO
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
Guide to Selecting Obesity Treatment
BMI
Treatment
Diet
Exercise
Pharmacology
Surgery
<25
25-26.9
27-29.9
30-35
35-40
>40
+
+
+
+
+
w/ comorbidities
+
+
+
w/ comorbidities
+
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
24
22
20
18
16
14
12
10
8
6
4
2
0
o.
m
o.
m
o.
m
o.
m
o.
m
o.
m
o.
m
o.
m
o.
m
o.
m
o.
m
o.
m
o.
m
Fenfluramine
1-Year Rx & 1-Year Follow-up
30
25
20
Pounds
15
10
5
0
Chronic Disease Drug Development
Obesity
Hypertension
►
►
►
►
Diuretics – salt in urine
CNS drugs – side effects
eg. reserpine and
depression
Combinations to lower
side effects and increase
efficacy
Peripherally acting drugs
eg. angiotensin receptor
blockers
►
Orlistat – calories in stool
►
CNS drugs – side effects
eg. amphetamine and
addiction
►
Combinations to lower
side effects and increase
efficacy eg topiramatephentermine
►
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
Weight Loss Drugs Approved by FDA
Generic Name
Trade Name
Phentermine/Topiramate
Lorcaserin
Orlistat
Phentermine
Diethylpropion
Phendimetrazine
Qsymia
Belviq
Xenical, Alli
Adipex, Fastin, Ionamin
Tenuate, Tenuate, Dospan
Bontril, Plegine, Prelu-2,
X-Trozine
Desoxyn
Didrex
Sanorex, Mazanor
Methamphetamine
Benzphetamine
Mazindol
Efficacy of Currently Available
Weight Loss Medications
Drug
Average Weight Loss
►
Phentermine
►
3.6% > placebo
►
Orlistat
►
2.75% > placebo
►
Lorcaserin
►
3.3% > placebo
►
Phentermine/Topiramate
►
9% > placebo
Phentermine
►
Mechanism:
●
●
Appetite suppressant
Inhibits NE and dopamine release
►
Dose: 15-37.5 mg daily (AM)
►
FDA approved for short-term (3 months) use
►
Side effects: Increased BP and HR, insomnia, agitation,
►
Efficacy: More weight loss than placebo (~3-5%)
dry mouth, headache, tremor
Orlistat
►
Mechanism: Inhibits lipases and blocks fat absorption by ~30%
►
Dose: 60-120 mg TID (with meals)
►
FDA approved for long-term use
►
Side effects: mild to moderate GI “events”, potential for
►
Efficacy:
(reduction in absorbed fat)
malabsorption of fat soluble vitamins, liver toxicity?, nephrolithiasis
●
●
●
●
●
More weight loss than placebo (~4%)
More lose at least 5% (35-69% vs 16-30% with placebo)
More lose at least 10% (16-25% vs 4-12% with placebo)
Prevention of diabetes incidence
Improvements in glycemic control in T2D
Lorcaserin
►
Brand name: Belviq
►
Approved in 2012 (10 mg BID) for long-term weight
management
►
Mechanism:
●
●
Selective 5-HT2C receptor agonist
increases satiety – appetite suppressant
Bays HE. Expert Rev Cardiovasc Ther. 2009;7:1429-1445; Belviq [prescribing information]. Woodcliff Lake, NJ:
Eisai; Inc. 2012.
BLOOM Study
Body Weight Over Years 1 and 2
2.16 ± 0.14%
5.81 ± 0.16%
BLOOM = Behavioral Modification and Lorcaserin for Obesity.
Smith SR, et al. N Engl J Med. 2010;363:245-256.
BLOOM Study
Body Weight Over Years 1 and 2
2.16 ± 0.14%
5.81 ± 0.16%
BLOOM = Behavioral Modification and Lorcaserin for Obesity.
Smith SR, et al. N Engl J Med. 2010;363:245-256.
BLOOM Study
Body Weight Over Years 1 and 2
47.5%
20.3%
22.6%
7.7%
BLOOM = Behavioral Modification and Lorcaserin for Obesity.
Smith SR, et al. N Engl J Med. 2010;363:245-256.
BLOOM-DM
Change in Glycemic Parameters
*
*
Fasting Plasma Glucose
*
*
Change From Baseline
(mg/dL)
Change From Baseline (%)
HbA1C, -0.5%
Study Week
Lorcaserin 10 mg twice a day
*
*
Study Week
Placebo
*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.
†
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
►
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
● Interesting effect on glycemia – greater benefit than
expected for degree of weight loss
Bays HE. Expert Rev Cardiovasc Ther. 2009;7:1429-1445; Belviq [prescribing information]. Woodcliff Lake, NJ:
Eisai; Inc. 2012.
Phentermine and Fenfluramine
Phen - Fen
Weintraub M et al. Clin Pharmacol Ther. 51(5):586-94, 1992.
Phentermine/Topiramate ER
►
Brand name: Qsymia
►
Approved in 2012 for long-term weight management
►
Mechanism:
●
●
●
►
Phentermine: inhibits NE and dopamine release
Topiramate: mechanism on weight loss is not known
Increases satiety – appetite suppressant
Dosing:
●
●
Start at 3.75/23mg daily x 2 weeks then↑to 7.5/46mg
After 12 weeks can↑to 11.25/69mg and 15/92mg
Phentermine/Topiramate Phase III Trial
Gadde KM et al. Lancet. 2011;377(9774):1314-52
Phentermine/Topiramate Phase III Trial
Gadde KM et al. Lancet. 2011;377(9774):1314-52
Phentermine/Topiramate Phase III Trial
Garvey, et al. Am J Clin Nutr 2012;95:297-308.
Phentermine/Topiramate ER
►
Most common AEs: paresthesias, dizziness,
dysgeusia, insomnia, constipation and dry mouth.
►
Other AEs:  BP and HR, headache, suicidal thoughts,
myopia/secondary angle closure glaucoma, cognitive
impairment, metabolic acidosis,↑creatinine
►
Notes
●
●
●
●
Discontinue if 5% weight loss is not achieved by week 12
DEA Schedule Class IV
Pregnancy category X
Safety: fetal cleft palate - pregnancy test q mo.
Obesity Drugs and CVD Risk Factors
Anti-Obesity
Agent
Phentermine/
Topirmate ER
Lorcaserin
BP
LDL-C
TG
HDL-C





No
significant
change


Bays HE. Specialty Corner: Investigational Anti-obesity Agents to Treat Adiposopathy and "Sick Fat.”
pages 22-23. 2011
New Frontiers and Treatment Paradigms for
Pharmacologic Management of Obesity
What’s in the Pipeline?
Naltrexone/Bupropion
►
Not yet FDA approved
►
CVD safety study in progress
►
Dose: 3 week escalation to 16/180mg SR bid
►
Mechanism:
●
●
●
►
Naltrexone: opioid receptor antagonist
Buproprion: NE/dopamine reuptake inhibitor
Appetite suppressant, reduces cravings?
Adverse events : Nausea, headache, constipation,
dizziness, vomiting, insomnia, dry mouth & hot flushes
Bupropion 360 & Naltrexone 32 mg
Placebo (N=511)
NB16 (N=471)
NB32 (N=471)
Placebo
Completers (N=290)
0
-1.3%
-2
-4
-5.0%
-6.1%†
-6
-8
-10
0
8
16
24
32
40
48
56
NB32
Completers (N=296)
Completers
Observed
Change from baseline (%)
Change from baseline (%)
ITT-LOCF
NB16
Completers (N=284)
0
-1.8%
-2
-4
-6
-6.7%
-8
-10
-8.1%
0
Week
Placebo-subtracted weight loss
Week 56
NB16: -3.7%
NB32: -4.8%
8
16
24
32
40
48
56
Week
Placebo-subtracted weight loss
Completers
NB16: -4.9%
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
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%
-2%
-1.2%
-3%
-4%
Mean Weight Loss
-5%
-6%
-7%
-8%
-9%
-10%
-11%
-12%
-13%
-10.9%
-11.6%
-12.1%
-12.5%
-12.9%
-14%
-15%
-14.9%
-16%
(a) Placebo weight loss through 24 weeks as noted previously
Beloranib
►
Methionine Aminopeptidase 2 (MetAP2) Inhibitor
●
●
●
●
METAP2 is an enzyme which plays a key role in
the production and use of fatty acids
Reduced food intake?
Reduced lipogenesis?
Increased lipolysis?
Belornib - Body Weight in Mice
Body weights during the course of 1 mg/kg/day fumagillin (ZGN-201) treatment
60
55
50
Body Weight
(grams)
Chow-Fed Control
High Fat Diet Control
45
High Fat Diet + ZGN-201
40
35
30
25
0
30
60
90
120 150 180
Day of Study
210
240
270
Belornib – Weight Loss in Humans
►
Impact of 2-18 ug/kg/dose ZGN-433 treatment on body weight in obese women
Values are medians ± SEM (n=6-8) for the per protocol population.
*** p<0.001 by 2-way ANOVA and Bonferroni post-test.
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 are being developed but may be
limited by side effects.
►
There is significant variability in the weight loss response,
so important to consider predictors of response as we
move forward
Investigations  Stratification
Front Line Clinical Applications
Real World Challenges in
Obesity Management
Case Study-Based Learning Workshops and Clinical
Simulations in Obesity Management
MARC-ANDRE CORNIER, MD - Program Chairman
Associate Professor of Medicine
Division of Endocrinology, Metabolism and Diabetes
Anschutz Health and Wellness Center
University of Colorado School of Medicine
Denver, CO
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
Case Study 1 - Question 2
 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.
 At this point you would:
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
Please Enter Your Response On Your Keypad
Case Study 1 - Question 3
 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.
 At this point you would:
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
Please Enter Your Response On Your Keypad
Case Study 1 - Question 4
 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.
 At this point you would:
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
Case Study 2 - Question 1
You increase the dose of simvastatin.
What would you do to treat the obesity?
1. Recommend a healthier and more regular diet
2. Encourage a more vigorous exercise program
3. Refer him to a psychologist for behavior
modification
4. Initiate orlistat therapy
5. Initiate lorcaserin therapy
Please Enter Your Response On Your Keypad
42 M
BMI 37
Central distribution
Pre-DM
Dyslipidemia
GERD
Gout
OA
Childhood onset
Steady adult gain
Irregular eater
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
Please Enter Your Response On Your Keypad
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%
Case Study 2 – Question
3
What would you do now?
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
Please Enter Your Response On Your Keypad
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%)
Case Study 2 - Question 4
What would you do now?
1. Continue the phentermine at 15 mg/day and reemphasize 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
Please Enter Your Response On Your Keypad
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
Case Study 2 - Question 5
What would you do now?
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
5. Recommend consultation for bariatric surgery
Please Enter Your Response On Your Keypad
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
Case Study 2 - Question 6
What would you do now?
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
5. Recommend consultation for bariatric surgery
Please Enter Your Response On Your Keypad
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 (longand 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
• Central obesity with waist circumference 41 in.
• 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
• Other tests normal
Case Study 3
Weight and lifestyle history
• 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
Case Study 3 - Question 1
You increase the dose of L-thyroxine.
How would you initiate obesity treatment?
1. Recommend a meal-replacement program
2. Substitute citalopram for sertraline
3. Refer her to a psychologist for cognitivebehavior therapy for the depression
4. Substitute metformin for glimepiride
5. Initiate treatment with a combination of
phentermine and topiramate
Please Enter Your Response On Your Keypad
51 F
BMI 43.3
Central distribution
T2DM (55
OSA
Hypothyroidism
GERD / Barrett’s
OA
Colonic polyps
Depression
Adult onset
Healthy diet
Often hungry
Large portions
Regular exerciser
Case Study 3
Clinical progress
• You discontinue the sulfonylurea and start metformin at 500
mg bid, monitoring her glucose carefully and adjusting shortacting 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%)
Case Study 3 - Question 2
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
Please Enter Your Response On Your Keypad
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.
Case Study 3 - Question 3
What would you do now?
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
Please Enter Your Response On Your Keypad
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%
Case Study 3 - Question 4
What would you do now?
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
Please Enter Your Response On Your Keypad
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)
Case Study 3 - Question 5
What would you do now?
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 lorcaserin
5. Refer her back to the surgeon for consideration of revising the
surgical procedure
Please Enter Your Response On Your Keypad
Case Study 3
Clinical progress
• Lorcaserin at 10 mg/day is started and well-tolerated
• Over the next 6 months, she loses an additional 15 lbs.
to a weight of 164 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
• Central obesity with waist circumference 36 in.
• BP 134/90
Laboratory studies
• Glucose 118; HbA1c 6.4%
• Triglycerides 255 mg/dL, LDL cholesterol 140
• HDL cholesterol 42 mg/dL
• Other tests normal
Case Study 4
Weight and lifestyle history
• 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
Case Study 4 - Question 1
What treatment would you initially
recommend for this patient?
1. Broad-based diet and lifestyle counseling
2. Implementation of moderate structured
exercise regimen
3. Cooking classes
4. Change jobs
5. Initiate pharmacotherapy for obesity
Please Enter Your Response On Your Keypad
46 F
BMI 30.7
Central distribution
Pre-DM
HTN
Dyslipidemia
GERD
Joint pain
Obesity onset 20s
Failed diets
Home-cooker
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)
Case Study 4 – Question
2
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
Please Enter Your Response On Your Keypad
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
Case Study 4 – Question
3
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
Please Enter Your Response On Your Keypad
Investigations  Stratification
Front Line Clinical Applications
Summary and Vision Statement
Near Term Challenges and Potential Strategies for
Optimizing Obesity Management in the Primary
Care Setting
Summary
►
Obesity is a chronic physiologically controlled disease that
requires chronic treatment
●
►
Must be approached like other chronic diseases
Yes, there are still many barriers and challenges to
overcome with the management of obesity
●
But there are also many opportunities
►
Awareness and education are critical!
►
Lifestyle modification is at the core of all our therapeutic
options
►
We have good pharmacotherapies and new agents on the
horizon yet these are underused
►
We must use all of the tools at our disposition
Summary
►
Reasons Why You Should Treat OverweightObesity
●
Excess adiposity adversely impacts health
●
Obesity is a medical condition with a physiologic
and behavioral component like many other
chronic medical conditions we routinely treat on
an ongoing basis in primary care
●
Our patients are asking for help
●
If you don’t, then who will?
Investigations  Stratification
Front Line Clinical Applications
Questions and Answers