Please Take A Moment to Complete the Pre-Program Clinical Performance and
Knowledge Gap Assessment Survey
Investigations  Stratification
Front Line Clinical Applications
New Perspectives and Emerging Treatment Paradigms for
Individualizing Obesity Management
Focus on Maximizing Behavioral, Cardiometabolic, and
Weight Loss Outcomes with Pharmacologic Agents Targeting
the Central Nervous System
Program Co-Chairs
Ken Fujioka, MD
Lee M. Kaplan, MD, PhD
Director, Nutrition and Metabolic Research
Center | Director, Center for Weight
Management | Scripps Clinic
San Diego, CA
Director, Obesity, Metabolism & Nutrition
Institute | Massachusetts General
Hospital | Associate Professor of Medicine
| Harvard Medical School | Boston,
Massachusetts
Welcome and Program Overview
CME-certified symposium jointly
sponsored by the University of
Massachusetts Medical School and
CMEducation Resources, LLC
Commercial Support: This CME
activity is supported by an
educational grant from Eisai, Inc.
Distinguished Faculty
Program Co-Chairman
Lee M. Kaplan, MD, PhD
Program Co-Chairman
Ken Fujioka, MD
Associate Professor of Medicine
Harvard Medical School
Director, Obesity, Metabolism &
Nutrition Institute
Massachusetts General Hospital
Boston, Massachusetts
Director, Nutrition and Metabolic Research
Center
Director, Center for Weight Management
Scripps Clinic
San Diego, CA
Louis J. Aronne, MD
Sanford I. Weill Professor of Metabolic
Research
Weill-Cornell Medical College
Attending Physician
The New York-Presbyterian Hospital,
Weill-Cornell Medical College
New York, NY
Robert F. Kushner, MD
Professor of Medicine
Northwestern University
Feinberg School of Medicine
Clinical Director, Northwestern
Comprehensive Center on Obesity
Chicago, Illinois
COI Disclosures
Faculty Member
Relationship
Corporation/Manufacturer
Kenneth Fujioka, MD
Consultant:
Orexigen, Novo Nordisk, Zafgen, NPS, Eisai,
Nazura, Pathway Genomics, Isis
Abbott, NPS, Eisai, Vivus
Orexigen, Novo Nordisk, Enteromedics, NPS,
Eisai, Weight Watchers
Speaker’s Bureau:
Grant/Research
Lee Kaplan, MD, PhD
Scientific Advisor:
Grant/Research:
Ethicon, Astra Zeneca, Eisai, GI Dynamics,
MedImmune, Novo Nordisk, Rhythm,
Takeda, Vivus, Zafgen
Ethicon
Robert F. Kushner, MD
Consultant:
Grant/Research
Novo Nordisk, Vivus, Retrofit
Weight Watchers, Aspire Bariatrics
Louis J. Aronne, MD
Consultant:
Eisai, Ethicon Endo-Surgery, Novo Nordisk,
Vivus, Zafgen
Medical University of South Carolina, Novo
Nordisk, GI Dynamics, Aspire Bariatrics
Cardiometabolic Support Network, LLC,
Myos Corporation, Zafgen
Myos Corporation
Grant/Research:
Ownership Interest:
Board of Directors:
New Perspectives and
Emerging Treatment Paradigms
Current Challenges and Barriers to
Obesity Treatment in the
Primary Care Setting
Ken Fujioka, MD – Program Co-Chair
Director, Nutrition and Metabolic Research Center | Director, Center
for Weight Management | Scripps Clinic in San Diego, CA
Are you Biased Against
Overweight Patients?
►
Fat people are good and lazy; thin people are
bad and motivated
►
Fat people are bad and motivated; thin
people are good and lazy
►
Fat people are bad and lazy; thin people are
good and motivated
►
Fat people are good and motivated; thin
people are bad and lazy
Are you Biased ?
►
Anywhere from 30% to 40% of health care providers
who specialized in obesity treatment answered:
Fat people are bad and lazy; thin people are good
and motivated
●
●
Indicating bias or negative attitudes towards the
overweight and obese patient
Much of this bias is related to a lack of knowledge
Teachman BA, Brownell KD. Int J Obes Relat Metab Disord. 2001;25(10):1525-1531.
Knowledge of Obesity
►
Lack of knowledge is cited by many studies as a
reason why health care professionals do not even
attempt obesity management
►
Not surprising
●
Understanding the mechanism of why it is so hard to lose
weight and keep it off is recent
Fujioka K, Bakhru N. Office based management of Obesity;. Mt Sinai J Med. 2010 Sep-Oct;77(5):466-71. Review.
Pathophysiology of Obesity
Why is it So Hard to Lose Weight?
►
Need to know how humans regulate weight to
understand the treatment options
►
Patient A
●
●
●
●
48-year-old with a sedentary job
Weight - 150 pounds
Develops lower back pain and is placed on prednisone
(steroids) to decrease inflammation in compressed nerve
causing severe pain
Patient on “the steroids” for 2 months and unable
exercise for 6 months and gains 50 pounds
The Patient has Gained 50 pounds

The patient has gone from 150 pounds to 200 pounds
• With this weight gain his fasting blood sugar is now 105

The patient is now a “pre-diabetic”
• If the patient is Asian or Hispanic, he will see prediabetes emerge with less weight gain (20 to 30
pounds)

The patient is now technically obese
Motivated Patient Trying to Lose Weight
►
The patient recovers from the back injury and decides to
lose weight
►
The patient begins a diet and exercise program
►
He loses about 20 pounds (over 3 months)
●
200 down to 180
►
Despite staying on the diet and exercising 2 to 3 days a
week, the patient stops losing weight
►
A few months later the patient notes that weight is
starting to slowly go up
Weight Regulation in Humans
►
The human body is hardwired to know how many fat
cells are on board and to keep the body weight stable
►
At about 5% to 10% of weight loss the human body
will respond by:
●
●
●
●
Lowering metabolic rate (more than 5%-10%)
Lower the hormones that signal satiety or fullness after
eating
Increase thoughts and hormones to make humans seek out
and eat more food
All part of defense of body weight
• This does not get better with time (always trying to get back to that
highest weight)
Sumithran P et al. N Engl J Med. 2011;365:1597-1604
The Good News on
5% to 10% Weight Loss
►
Sustained weight loss of 3%-5% is likely to result in
clinically meaningful reductions in triglycerides,
blood glucose, HbA1C, and the risk of developing
type 2 diabetes
►
Greater amounts of weight loss will reduce blood
pressure, improve LDL–C and HDL–C, and reduce the
need for medications to control blood pressure,
blood glucose and lipids as well as further reduce
triglycerides and blood glucose
Jensen MD, et al.
2013 AHA/ACC/TOS Obesity Guideline
Treatment Options
2012
Diet
• Meal replacements, VLCDs, standard low calorie diets
Exercise
• Just figured out that a combination of cardio and
resistance training is better
Phentermine
• Short term medication
Orlistat
• Fat blocker with limited efficacy and well known side
effects
Bariatric surgery
• Lap band
• Gastric bypass
Treatment Options
2014
►
Medications approved in 2013
●
●
►
Lorcaserin
Phentermine/Topiramate ER
Medications going to the FDA for possible
approval
●
●
Liraglutide
Bupropion SR/ Naltrexone SR
Proper Use of Obesity Medications
►
Recognizing non-responders
●
An obese patient is started on a weight loss
medication and is not losing adequate
amounts of weight
●
STOP the medication
• Lorcaserin patient should lose 5% or more of
their weight by 3 months, otherwise stop
• Phentermine/topiramate patient should lose
3% by 3 months or 5% by 6 months
REMs
Risk Evaluation Mitigation Strategy
►
Phentermine/Topiramate ER
●
►
Possible cleft lip or palate in fetus
exposed to topiramate
REMS
●
●
Physicians and pharmacies trained on use
of the medication
Only certified pharmacies can dispense
• Help to ensure the patient is educated to
not get pregnant while on the medication
Bariatric Surgery
►
Bariatric surgery
●
Sleeve gastrectomy comes of age
• Procedure between an adjustable band
and gastric bypass
• Excellent weight loss
• Fewer nutritional problems after
(compared to bypass)
Financial
►
AMA – Obesity defined as a “disease”
►
CMS – Primary care practitioners (includes NPs and
PAs) can get reimbursed for “obesity treatment”
●
►
Weight loss medications
●
►
They have specific guidelines on how to treat
More insurance companies are now starting to
reimburse for weight loss medications
• The overall number is still low (less than 50%)
Bariatric surgery
●
Vast majority of insurances cover
New Perspectives and Emerging Treatment Paradigms
for Individualizing Obesity Management
Treating Patients with Obesity:
Who, Why, How and to What Ends
Lee M. Kaplan, MD, PhD
Obesity, Metabolism & Nutrition Institute
Massachusetts General Hospital
Harvard Medical School
LMKaplan@partners.org
April 11, 2014
Disclosures
I receive funding for basic research from the U.S. National
Institutes of Health and Ethicon Surgical Care.
I am a member of scientific advisory boards for the following
companies:
Astra-Zeneca
Gelesis
Novo Nordisk
USGI Medical
Eisai
GI Dynamics
Rhythm
Vivus
Ethicon
MedImmune
Second Genome
Zafgen
Fractyl
Metavision
Takeda
I have equity in the following companies:
Fractyl
GI Dynamics
Gelesis
Rhythm
I may discuss the off-label / unapproved use of several drugs or
devices, including: bupropion, canagliflozin, EndoBarrier,
exenatide, liraglutide, metformin, naltrexone, phentermine,
pramlintide, topiramate, zonisamide
Question 1
Why is weight regain after dieting so common?
1. Exercise, not diet, is the most effective means of losing
weight
2. The body reacts to weight loss by decreasing daily
energy expenditure
3. Diet foods are boring and patients stop eating them
4. Dieting increases the body’s set point for fat mass
5. Weight loss often leads to unwanted effects that
cause patients to sabotage their efforts
Please Enter Your Response On Your Keypad
Question 2
Which of the following is NOT a demonstrated
benefit of modest regular exercise?
1. Enhances weight loss effect of other lifestyle
changes
2. Causes weight loss directly
3. Alters appetite to favor healthier foods
4. Stimulates fat to burn more calories
5. Decreases cardiovascular risk
Please Enter Your Response On Your Keypad
Question 3
Which of the following comorbidities of
obesity has NOT been shown to improve with
modest (5-10%) weight loss?
1. Type 2 diabetes
2. Hypertension
3. Dyslipidemia
4. Cardiovascular risk
5. Fatty liver disease
Please Enter Your Response On Your Keypad
Question 4
If a patient with prediabetes and obesity maintains a
4% weight loss over 4 years, how much do they lower
their risk of developing diabetes?
1. <10%
2. ~25%
3. ~50%
4. ~75%
5. >90%
Please Enter Your Response On Your Keypad
Question 5
Which of the following medications is NOT currently
approved by the FDA for the treatment of obesity?
1. Orlistat
2. Liraglutide
3. Phentermine
4. Lorcaserin
5. Phentermine / Topiramate ER combination
Please Enter Your Response On Your Keypad
Question 6
Which of the following weight loss
medications do NOT work through central
nervous system mechanisms?
1. Bupropion
2. Lorcaserin
3. Liraglutide
4. Topiramate ER
5. Phentermine
Please Enter Your Response On Your Keypad
Question 7
Which of the following is NOT a primary
mechanism of weight loss from centrallyacting weight loss medications?
1. Change in food preferences
2. Decrease in appetite
3. Increase in resting and post-meal energy expenditure
4. Demonstrating the value of a healthier weight to the patient
5. Lower physiologically defended body weight
Please Enter Your Response On Your Keypad
Medical Complications of Obesity
Stroke
Pulmonary disease
abnormal function
obstructive sleep apnea
hypoventilation syndrome
Pancreatitis
Fatty liver
disease
steatosis
steatohepatitis
cirrhosis
Gallstones
Cancer
breast, uterus, cervix, ovary,
prostate, kidney, colon, esophagus
pancreas, gallbladder, liver
Skin disorders
Gout
Intracranial hypertension
Cognitive dysfunction
Cataracts
Coronary heart disease
Diabetes
Dyslipidemia
Hypertension
Gynecologic abnormalities
abnormal menses
infertility
polycystic ovarian syndrome
Osteoarthritis
Phlebitis
venous stasis
Complications of Obesity
Metabolic
Structural
Inflammatory
Degenerative
Neoplastic
Psychological
65
Complications of Obesity
Metabolic
Structural
Inflammatory
Degenerative
Neoplastic
Psychological
Several of these complications exacerbate the
underlying obesity, creating a vicious cycle:
Diabetes
Many diabetes drugs
cause weight gain
PCOS
Insulin resistance
promotes lipogenesis
Sleep apnea
Disrupted sleep
can cause weight gain
Arthritis
Back pain
Limit exercise capacity
Inflammatory
disorders
Steroids often cause
weight gain
Depression
Psychological
Eating disorders and
many psychotropic agents
cause weight gain
Benefits of Modest Intentional Weight Loss
• Improvement in comorbid
diseases
• Type 2 diabetes
• Hypertension
• Dyslipidemia
• Fatty liver disease
• Obstructive sleep apnea
• Asthma
• Osteoarthritis
• Cancer risk
• Improved quality of life
• Decreased health care costs
• Decreased surgical
complication rates
• Orthopedic surgery
• Heart surgery
• General and thoracic
surgery
• The effect on cardiovascular risk is less clear
Age-Adjusted Relative Risk
Relationship Between BMI and
Risk of Type 2 Diabetes
93.2
Men
Women
54.0
42.1
40.3
27.6
21.3
1.0
2.9
1.0
<22
<23
5.0
1.5
4.3
1.0
8.1
2.2
15.8
4.4
6.7
11.6
23-24 24-25 25-27 27-29 29-31 31-33 33-35
Body Mass index (kg/m2)
Chan J et al. Diabetes Care 1994;17:961.
Colditz G et al. Ann Intern Med 1995;122:481.
>35
Benefits of Intensive Medical Intervention
Diabetes Prevention Program
Change in Weight (kg)
6
2
-2
-6
-10
Placebo
Metformin
Lifestyle
-14
-18
-22
0
0.5
1
1.5
2
Year
DPP Research Group, N Engl J Med, 2002
2.5
3
3.5
4
Diabetes Prevention
Cumulative Incidence
of Diabetes (%)
40
Placebo
30
Metformin
20
Lifestyle
10
0
0
1
2
Year
Diabetes Prevention Program Research Group
N Engl J Med, 2002
3
4
Obesity results from a failure of normal weight and
energy regulatory mechanisms
Obesity: A Failure of Weight Regulation
Cortex
Genetics
Development
Environment
HT
GI Tract
Food intake
Leptin
Energy expenditure
Nutrient handling
Adipose
tissue
The current obesity epidemic results
primarily from changes in the environment
Macroenvironmental Influences*
• 24-hour lifestyle
• Economic structure
• Time pressures
• Workload
• Loss of downtime
• Speed of life
• Global stressors
*Amenable only to societal intervention
Microenvironmental Influences*
• Types of nutrients
• Eating schedules
• Physical activity
• Sleep health
• Drugs and medications
• Local stressors
*Amenable to individual action
The goal of lifestyle-based therapies is to
normalize the patient’s microenvironment
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
Lifestyle Treatment of the Patient with Obesity
• Healthy diet – to change the nutrient environment by changing
the diet chemistry
• Improves nutrient signaling to the brain
• Emphasize unprocessed foods
• Encourage complexity
• Number of calories is MUCH less important
• Regular exercise
• To improve muscle health, not to burn calories acutely
• Long-term exercise more important than type or intensity
• Stress reduction
• Reduce both perceived and “invisible” stresses
• Restore sleep
• Regularize circadian rhythms
Pharmacological Therapies
Medication-induced Weight Gain
Medications account for 5-10% of obesity in the U.S.
In each relevant category, remove or substitute
weight gain-promoting medications with weight
neutral or weight loss-promoting alternatives
Weight Loss from Other Medications
Strategy: Aim for Double Benefits when Possible
Medication
Indicated Uses
Comments
Bupropion
Depression
Avoid in bipolar disease
Topiramate
Seizures
Migraines
Mood disorders
May produce neurological side
effects
Zonisamide
Seizures
Mood disorders
Few studies
Metformin
Type 2 diabetes
PCOS
Rare liver toxicity
Liraglutide. Exenatide
Type 2 diabetes
Injectable
Pramlintide
Type 2 diabetes
Injectable
Pramlintide
Type 2 diabetes
Injectable
Medications Approved for Obesity
Medication
Average
Weight Loss*
Mechanism of
Action
Potential Side Effects
Phentermine (shortterm treatment)
~ 5%
Adrenergic
Tachycardia, hypertension
Phentermine /
Topiramate
10%
Adrenergic, CNS
Tachycardia, hypertension,
cognitive dysfunction,
neuropathy, teratogenicity
Lorcaserin
3.5%
Serotonergic
(5HT2C)
Headache
3%
Lipase inhibitor
Steatorrhea, incontinence
Orlistat
* Beyond placebo
Practical Use of Weight Loss Medications
• Understand risks, cautions and monitoring essentials
• Start when weight is stable (within 3% over 3 months)
•
Aim for weight stability with lifestyle management
• Assess effects at 1 and 3 months
• Continue medication beyond 3 months if ≥ 5% total weight loss
•
Some use “4x3” rule - ≥ 4 lbs. weight loss/month x 3 months
• Weight plateau with increased hunger is expected
•
Medication still working if substantial weight regain absent
Foundational Role of the Central Nervous
System in Appetite Regulation
Robert Kushner, MD, FACP
Professor of Medicine
Northwestern University
Feinberg School of Medicine
rkushner@northwestern.edu
Disclosures
I am a consultant, speaker, advisor, or receive research support from:
Aspire Bariatrics
Novo Nordisk
Retrofit
Takeda Pharmaceuticals
VIVUS Inc.
Weight Watchers
Zafgen Inc.
Clinical Application
• “Doctor, I know I need to reduce my calories
and exercise more in order to lose weight. I
have done it more times that I would like to
admit. But I get hungry and its hard to stay on
a calorie reduced diet. What is it about my
metabolism that causes me to be so hungry?”
Model summarizing the 3 levels of control
over energy homeostasis
Woods, S. C. et al. J Clin Endocrinol Metab 2008;93:s37-s50
Gut Peptides that Regulate Appetite
Murphy KG, Bloom SR. Nature 2006;444:854-859
Ghrelin Signals Hunger
BR
LU
DI
Ghrelin
Level
(24 hour clock)
Adapted from Williams DL, Cummings DE. J Nutr 2005;135:1320-1325
Gut peptides and
regulation of appetite
Peptide
Where
synthesized
Effect on feeding
Ghrelin
Stomach
Orexigenic
CCK
Duodenum
Anorexigenic
PYY
Distal small
intestine
Anorexigenic
GLP-1
Small intestine
Anorexigenic
Amylin
Pancreas
Anorexigenic
CCK = cholecystokinin; PYY = polypeptide YY;
GLP-1 = glucagon-like peptide 1; [exenatide, liraglutide]; Amylin [pramlintide]
Model summarizing the 3 levels of control
over energy homeostasis
Woods, S. C. et al. J Clin Endocrinol Metab 2008;93:s37-s50
Leptin is reduced in response to reduction in
calories and weight loss; increasing appetite
BDD = balanced deficit diet (1200
kcal/d week 2 – 20, then 1200 – 1800
kcal/d week 21 – 40)
LCD = low calorie diet (1000 kcal/d
week 2 – 13, 1200 kcal/d week 14-20,
then 1200 – 1800 kcal/d weeks 21-40)
Wadden TA et al. J Clin Endocrinol Metab 1998;83:214-218
Model summarizing the 3 levels of control
over energy homeostasis
Woods, S. C. et al. J Clin Endocrinol Metab 2008;93:s37-s50
Effector Signaling Molecules
ob
gene
Fat Cells
ob
gene
Leptin
ob
gene
Hypothalamus
Anorexigenic
• CART
• POMC
•  MSH
Orexigenic
• Neuropeptide Y
• Agouti-related
protein
Adapted from: L. A. Campfield, F. J. Smith, P. Burn, Horm. Metab. Res. 28, 619 (1996);
Endocrinol. Metab. 4, 81 (1997).
Neuron Populations in the ARC
Two neuron populations with opposing effects on food
intake in the hypothalamic arcuate nucleus (ARC):
Stimulate food intake
• NPY (neuropeptide Y)
• AgRP (agouti-related peptide)
Suppress food intake
• POMC (proopiomelanocortin)
• CART (cocaine- and amphetamineregulated transcript)
Suzuki K, Jayasena CN, Bloom SR. J Obes. 2011; 2011: 528401. doi: 10.1155/2011/528401.
The Pivotal Role of Leptin
Reduce hunger
Increase hunger
Leptin activation of neurons in the arcuate nucleus
Leptin inhibits appetite through its actions on the appetite-stimulating neuropeptide Y
(NPY) neurons and the appetite-inhibiting POMC neurons, located in the hypothalamic
arcuate nucleus. Leptin inhibits the NPY/AgRP neurons by acting on its receptors and
causing a decrease in the release of the inhibitory neurotransmitter GABA. This causes
the POMC neurons to become free of inhibition and so they can increase their firing rate
leading to the production of alpha MSH - an inhibitor of appetite. Leptin also acts
directly on the POMC neurons.
University of Edinburgh http://www.diabesity.eu/Leptin.htm
Hypothalamic Appetite Regulation
Increased hunger
Reduced hunger
Farooqi S. Cell Metab 2006;4:260-262
Clinical Application
• Are some cases of severe obesity due to
defects in signaling and neuroregulation?
A Case of Congenital Leptin Deficiency
Farooqi et al. NEJM 341, 1999
Hypothalamic Appetite Regulation
6% children with
severe obesity had
a mutation in the
MC4 receptor
3% of subjects with
severe early onset
obesity had a LEPR
mutation
Farooqi S. Cell Metab 2006;4:260-262
Clinical Application
• Can we target some of these signals for
pharmacological intervention?
Hypothalamic Appetite Regulation
Adrenergic R
5-HT 2c R
Topiramate
Increased hunger
Reduced hunger
Farooqi S. Cell Metab 2006;4:260-262
Clinical Application
• “But doctor, sometimes I get cravings that I
can’t control. I’m not even hungry and I eat. I
feel like I am addicted to food!”
Berthoud HR. Curr Opin Neurobiology 2011;21:888-896
Regulation of Eating: Homeostatic
versus Hedonic Signaling Pathways
AN = arcuate nucleus. PVN = paraventricular nucleus, LHA = lateral hypothalamic area
VTA = ventral tegmental areas, SN = substantia nigra, DS = dorsal striatum, NAc = nucleus accumbens
Wang GJ et al. J Addict Med 2009;3:8-18
Activation of Regional Brain Areas by
Visual Images of Foods
Mehta S et al. Am J Clin Nutr 2012;96:989-999
Key Learning Take Away’s
from the Presentation
There are 2 peripheral signals that inform the brain about energy balance
Satiation signals arise from gut hormones and indicate meal-to-meal
hunger (ghrelin) and fullness (GLP-1, PYY)
Adiposity signals arise from fat cells (leptin) and monitor longer-term
energy balance
The ‘ying-yang’ hypothalamic system is balanced between 2 primary
neurons: NYP/AGRP (hunger) and POMC/CART (satiety)
Two new pharmacological agents (phentermine-topiramate and lorcaserin)
act on the primary neurons to alter neurotransmission
The hedonic signaling pathway is responsible to ‘liking or craving’ food
Results and Implications of Multicenter Trials Evaluating the Safety and Efficacy
of Centrally Acting Agents as part of Multimodal Management for Obesity
A Review of Metabolic Benefits, Side Effects, and
Rationale for Achieving Moderate Weight Loss Through
Drug Based Therapy
Louis J. Aronne, MD, FACP
Sanford I. Weill Professor of Metabolic Research
Weill Medical College of Cornell University
Medical Director, Center for Weight Management and Metabolic
Clinical Research
New York Presbyterian Hospital
New York, NY
March 2014
March 2014
Disclosures
I am a consultant, speaker, advisor,
or receive research support from:
Aspire Bariatrics
Amylin Pharmaceuticals Inc
Arena Pharmaceuticals
Eisai Inc.
Ethicon Endo-Surgery Inc.
GlaxoSmithKline Consumer Healthcare LP
GI Dynamics
High Point Pharmaceuticals LLC
Medical University of South Carolina
Novo Nordisk
Pfizer
Takeda Pharmaceuticals
USGI
VIVUS Inc.
Zafgen Inc.
As faculty of Weill Cornell Medical College, we are
committed to providing transparency for any and all external
relationships prior to giving an academic presentation.
Ownership Interest:
BMIQ
Cardiometabolic Support
Network
Myos Corporation
Zafgen, Inc.
Board of Directors:
Myos Corporation
Jamieson Laboratories
Obesity Pharmacotherapy
Obesity Pharmacotherapy
An adjunct to lifestyle modification
– not a substitute
Can increase chances of
meaningful weight loss
76
Anti-obesity Medications
Rationale and Criteria
• Non-drug interventions
should be attempted for at
least 6 months before
considering
pharmacotherapy1
• For patients with BMI > 30
• For patients with BMI > 27
or above with concomitant
risk factors or diseases
(hypertension, dyslipidemia, CHD,
type 2 diabetes, sleep apnea)1
1. NIH Clinical Guidelines Evidence Report, Sept 1998.
77
Hypertension Treatment
Lets think about for a minute:
>120 drugs in 10 categories
Up to triple drug combinations available
Diuretics
Beta-blockers
ACE inhibitors
Angiotensin II receptor blockers
Calcium channel blockers
Alpha blockers
Alpha-2 Receptor Agonist
Combined alpha and beta-blockers
Central agonists
Peripheral adrenergic inhibitors
Source: L. Aronne
78
Potential Anti-obesity Drugs and Their Pathways
Complex System with Redundancy-That’s Why It’s Hard to Lose
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
79
Anti-obesity Drugs Presently on the
Market and Pending Approval
FDA-Approved Drug Company
Mechanism of Action
Comments
Benzphetamine
(Didrex)
Pharmacia
Norepinephrine/dopamine
releasing stimulator
Schedule III drug, approved 1960
for short-term use
Phendimetrazine
(Bontril)
Valeant
Norepinephrine/dopamine
releasing stimulator
Schedule III drug, approved 1961
for short-term use
Phentermine
(Adipex, Suprenza)
Gates, Alpex
Noradrenaline/dopamine
releasing stimulator
Schedule IV drug, approved 1973
for short-term use
Watson Labs/
Corepharma
Norepinephrine/dopamine
releasing stimulator
Schedule IV drug, approved 1973
for short-term use
Roche, GSK
Pancreatic lipase inhibitor
Approved for long-term use in 1999
Diethylpropion
(Tenuate)
Orlistat
(Xenical) (Alli –OTC)
Phentermine/Topiramate
(Qysmia)
Vivus
(formerly Qnexa)
Noradrenaline releasing +
modulator of ɣ aminobutyric Approved July 2012
acid (GABA)/ carbonic
anhydrase inhibition
Lorcaserin
(Belviq)
Selective 5-HT2Creceptor
agonist
Arena Pharma
Approved June 2012
Anti-obesity Drugs that Await Decisions
Bupropion/Naltrexone
(Contrave)
Orexigen
Inhibitor of dopamine and
noradrenaline reuptake +
µ opiate antagonist
FDA requested data on long-term
cardiovascular risk assessment in 2011
Liraglutide
Novo Nordisk
GLP-1 agonist
Approved January 2010 for treatment of
Type 2 DM; phase III for anti-obesity at
higher doses
Modified from Zhi-yun Zhang Z-y and Wang M-w. Acta Pharmacologica Sinica 2012;33:145–147.
80
Expected Weight Loss with Newly Approved
and Investigational Anti-obesity Medications
Mechanism of
Action
Agent
Brand
Name
Drug
(kg)
Placebo
(kg)
Net Weight
Loss (kg)
Duration
FDA Approval
Selective serotonin
2C receptor
agonist
Lorcaserin
Belviq
8.2
3.4
4.8
52 weeks
June 2012
Qsymia
10.2
1.4
8.8
56 weeks
July 2012
Contrave
8.2
1.9
6.2
48 weeks
Application
Pending
Victoza
10.3±7.1
CombinationSympathomimetic/
gaba-ergic
migraine med
Combination
Antidepressant/
Opiate antagonist
Topiramate/
phentermine
Pending
Pending
Bupropion/
naltrexone
Pending for
obesity
Glucagon-like
peptide 1 (GLP-1)
Liraglutide
3.0 mg
104
weeks
Modified from Powell AG, Apovian CM, Aronne LJ. Clin Pharmacol Ther. 2011 Jul;90(1):40-51.
81
Recently Approved Pharmacotherapy
Agent
Phentermine/topiramate ER1,2
Qsymia™
Lorcaserin3,4
Belviq®
Approval
Status
Approved July 2012
Approved June 2012
Mechanism
PHEN noradrenaline and dopamine
releasing agent; TPM is an
anticonvulsant and GABA
modulator plus carbonic anhydrase
inhibitor
Selectively targets the
5-HT2C receptor
Follow-up
Duration
56 (108*) weeks
52 (104*) weeks
•
•
•
•
•
• Headache
• Dizziness
• Nausea
Common
Adverse
Effects
Dry mouth
Tingling
Constipation
Altered taste sensation
Upper respiratory infection
*2 year extension data available.
1. Gadde KM, et al. Lancet. 2011;377:1341-1352.
2. Garvey WT, et al. Am J Clin Nutr. 2012;95:297-308.
3. Smith SR, et al. N Engl J Med. 2010;363:245-256. 4. O’Neil PM, et al. Obesity. 2012;20:1426-1436.
82
Emerging Pharmacotherapy
Naltrexone/BupSR1
Contrave ®
Agent
Approval Status
Mechanism
FDA requested additional
Phase 3 data
Naltrexone: opioid receptor
antagonist
Bupropion: norepinephrinedopamine reuptake inhibitor
Liraglutide2,3
? Trade name
In Phase 3 clinical
trials
Glucagon-like
peptide-1 analogue
Follow-up Duration
56 weeks
56 weeks
Common AEs
•
•
•
•
•
•
•
•
•
Nausea
Headache
Constipation
Dizziness
Vomiting
Dry mouth
Nausea
Vomiting
Gastro-intestinal
effects
Clinicaltrials.gov. Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With
Cardiovascular Risk Factors (The Light Study). 2012.; Clinicaltrials.gov.
Effect of Liraglutide on Body Weight in Non-diabetic Obese Subjects or Overweight Subjects With Co-morbidities: SCALE Obesity and Pre-diabetes. 2011.
83
2012
Phentermine/Topiramate
Phentermine/Topiramate ER
Mechanism of
Action
Indications
and Dose
Contraindications
and Warnings
Phentermine
• Sympathomimetic
amine, NE release
•Approved by FDA,
Contraindications
July 2012, schedule IV
Pregnancy, glaucoma,
hyperthyroidism, MAOIs
• Blunts appetite
Weight loss in pts
with BMI ≥30 kg/m2
or BMI ≥27 kg/m2
with weight-related
co-morbid condition(s)
Topiramate
• Increases GABA
activity, antagonize
AMPA/ kainate
glutamate receptor,
carbonic anhydrase
inhibitor
• Prolongs satiety
•Indication
•Treatment Dose Daily
phentermine 7.5 mg
topiramate ER 46 mg
•Max Dose Daily
phentermine 15 mg
topiramate ER 92 mg
Warnings
• Fetal toxicity
• Increased heart rate
• Suicide and mood
and sleep disorders
• Acute myopia and
glaucoma
• Cognitive impairment
• Metabolic acidosis
• Creatinine elevations
• Hypoglycemia with
diabetes meds
Phentermine and topiramate extended-release [package insert]. Mountain View, CA : Vivus; 2012.
85
Phentermine/Topiramate ER
•
•
Once-a-day, oral, extended release topiramate
Low doses of previously approved medications to minimize side effects
23 46
Maximum
Approved
Doses
92
Topiramate ER
0
50
10
0
150
200
250
300
350
400 mg
Phentermine
0
3.75
Low
5
7.5
Mid
10
15
Full
20
25
30mg
(free base)
DOSING
• Begin with low dose for 2 wks phentermine 3.75/ topiramate ER
• Advance to treatment dose phentermine 7.5/ topiramate ER 46
• If <3% weight loss after 12 wks, either discontinue or advance to full dose phentermine
15/ topiramate ER 92 (transition dose phentermine 11.25/ topiramate ER 69 for 2 wks)
• If <5% weight loss after 12 wks on full dose, discontinue (take every other day for one wk)
Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012.
86
Phentermine/
Topiramate
Trials
EQUIP
CONQUER
SEQUEL
• Double-blind, placebo-controlled, three-arm, prospective study
• Extension of CONQUER Trial
• Same treatment as CONQUER study in a blinded fashion: either once-a-day
treatment with 15 mg QNEXA (n=295), 7.5 mg QNEXA (n=153), or placebo (n=227)
• 108-week treatment period, all patients were advised to follow a simple lifestyle
modification program including reduction of food intake by 500 calories per day
www.qsymia.com/hcp/conquer-trial.aspx
87
Effect of Phentermine/Topiramate ER on
Weight Loss in Obese Adults Over 2 Years
SEQUEL Study
Placebo -1.8%
Phentermine/topiramate CR 7.5/46 -9.3%
-10.5%
Phentermine/topiramate CR 15/92
Data are shown with least squares mean (95% CI).
Garvey WT, et al. Am J Clin Nutr. 2012;95:297-308.
88
Phentermine/Topiramate ER Improves Risk Factors
and Manifestations of Cardiometabolic Disease
CONQUER Study
Changes from baseline to week 56 in secondary endpoints
Variable
Phentermine
7.5mg/
Topiramate
46 mg ER
Placebo
P value
Waist circumference (cm)

-7.6
-2.4
<0.0001
Systolic BP (mm Hg)

-4.7
-2.4
0.0008
-3.4
-2.7
0.1281
-8.6
4.7
<0.0001
-3.7
-4.1
0.7391
Diastolic BP (mm Hg)
Triglycerides (%)

LDL–C (%)
HDL–C (%)

5.2
1.2
<0.0001
CRP (mg/L)

-2.49
-0.79
<0.0001
Adiponectin (µg/mL)

1.40
0.33
<0.0001
Gadde KM, et al. Lancet. 2011;377(9774):1341-1352.
89
Metabolic Effects of Phentermine/Topiramate
ER in Non-Diabetic Patients: SEQUEL Study
Glucose
*
Insulin
*
*
*
*
Placebo
Phen/TPM ER 7.5/46 mg
*
Phen/TPM ER 15/92 mg
*P≤0.005 vs placebo.
Phen/TPM CR, phentermine/topiramate controlled release.
Garvey WT, et al. Am J Clin Nutr. 2012;95:297-308.
90
Phentermine/Topiramate ER: EQUIP and CONQUER
Most Commonly Reported Treatment Emergent Adverse Events
Placebo
PHEN/TPM ER
3.75/23
PHEN/TPM ER
7.5/46
PHEN/TPM ER
15/92
Paresthesia
1.9
4.2
13.7
19.9
Dry mouth
2.8
6.7
13.5
19.1
Constipation
6.1
7.9
15.1
16.1
Upper respiratory
tract infection
12.8
15.8
12.2
13.5
Headache
9.3
10.4
7.0
10.6
Dysgeusia
1.1
1.3
7.4
9.4
Nasopharyngitis
8.0
12.5
10.6
9.4
Insomnia
4.7
5.0
5.8
9.4
Dizziness
3.4
2.9
7.2
8.6
Sinusitis
6.3
7.5
6.8
7.8
Nausea
4.4
5.8
3.6
7.2
Back pain
5.1
5.4
5.6
6.6
Fatigue
4.3
5.0
4.4
5.9
Blurred vision
3.5
6.3
4.0
5.4
Diarrhea
4.9
5.0
6.4
5.6
Adverse Event (%)
(N=3749)
Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012.
91
Summary of Phentermine and Topiramate
Neuropsychiatric Safety
• No serious AEs related to depression,
anxiety or cognition
• No increase in the risk of suicidality
(C-SSRS*, PHQ-9**, and AE reporting) in a
population where 20% had a prior history
of depression
• Can be prescribed in patients with stable
depression and patients on SSRIs
*Columbia Suicide Severity Rating Scale
** Patient Health Questionnaire 9-item depression scale
Phentermine and topiramate extended-release [package insert]. Mountain View, CA : Vivus; 2012.
92
Phentermine/Topiramate ER
REMS Program
FDA Pregnancy Category X: Contraindicated
• Topiramate monotherapy for epilepsy in
pregnancy associated with 2- to 5-fold increased
prevalence of oral clefts
Risk Evaluation and Mitigation Strategy (REMS)
• Inform patients about increased risk of orofacial
clefts, in infants exposed to phentermine/
topiramate during the first trimester of pregnancy
• Importance of contraception in women of childbearing potential and pregnancy checks
• Need to discontinue phentermine/topiramate
immediately if pregnancy occur
Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012.
Phentermine and topiramate extended-release capsules CIV Healthcare Provider Training Program. Vivus; 08/2012.
93
2012
Lorcaserin
Lorcaserin
Mechanism of
Action
Indications and
Dose
Contraindications
and Warnings
• Selective 5-HT2C
• Approved by FDA
Contraindications
• Pregnancy
receptor agonist
• Stimulates α-MSH
production from
POMC neurons
resulting in activation
of MC4R
• Increases satiety
June 2012
• Indication: Weight
loss in patients with
BMI ≥30 kg/m2 or
BMI ≥27 kg/m2 with
weight-related comorbid condition(s)
Warnings
• Co-administration with
other serotonergic or
anti-dopaminergic
agents
• Valvular heart disease
• 10 mg po bid
• Cognitive impairment
• Schedule IV
• Psychiatric disorders
• Discontinue if 5%
weight loss is not
achieved in 12 wks
(euphoria, suicidal
thoughts, depression)
• Priapism
• Risk of hypoglycemia
with diabetes meds
Lorcaserin hydrochloride [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012.
95
Proposed Model of a Serotonergic
Pathway Modulating Food Intake
Increase in serotonin bioavailability (due to food intake
or pharmacological compounds such as sibutramine
and fenfluramine) or direct agonism of 5HT2CRs and
5HT1BRs modulates firing of POMC/CART and AgRP
NPY neurones within the arcuate nucleus of the ARC
Anorectic POMC neurones expressing 5HT2CR
depolarize on receptor activation and release αmelanocyte-stimulating hormone (α-MSH), which in turn
activates second-order melanocortin 4 receptor (MC4R)
expressing neurones, principally within the
paraventricular nucleus of the hypothalamus
(PVH; Balthasar et al. 2005)
Concomitant activation of 5HT1BRs expressed on
orexigenic AgRP/NPY neurones within the ARC causes
membrane hyperpolarization and subsequent inhibition
of neuropeptide release
Inhibitory 5HT1BR activation also attenuates inhibitory
postsynaptic currents onto POMC/CART neurones
further potentiating anorexigenesis
Subsequent downstream neuroendocrine signalling
promotes satiety and the cessation of food intake
Garfield A S , and Heisler L K. J Physiol. 2009;587:49-60.
96
Lorcaserin Phase 3 Trials
• n=3,182
• 2 years tx
• Dosage 10 mg QD1
•
•
•
n=4,008
1 year tx
Dosage 10 mg QD2
1. Smith SR, et al. N Engl J Med 2010;363:245-56.
2. Fidler MC, et al. J Clin Endocrinol Metab, October 2011, 96(10):3067–3077.
3. O’Neil PM, et al. Obesity (16 March 2012) | doi:10.1038/oby.2012.66
Arena Pharmaceuticals
• n=604 obese/ overweight
with type 2 DM
• 1 year+ tx
• Dosage 10 mg BID
or 10 mg QD3
97
Lorcaserin: Those Who Lost ≥ 4.5% Total Body
Weight by Week 12 Were Week 52 Responders
Studies 009 and 011, MITT
0
Non-responder: Lorcaserin BID
-2.46%
STOP
-5
%
Change
-10
-10.22%
Responder: Lorcaserin
BID
-15
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Week
MITT Lorcaserin BID
Week
12
Responder:
Completed Week
12
Completed Week 52
Non-Responder:
N = 3097
Lorcaserin
BID
≥4.5%
wt loss
Lorcaserin BID
1369/3097 (44.2%)
1083/1369 (79.1%)
<4.5% wt loss
1168/3097 (37.7%)
Slide courtesy Dr. Steve Smith; May 10, 2012 FDA Advisory Committee Meeting
680/1168 (58.2%)
98
Lorcaserin ─ BLOOM Study:
Key Secondary Endpoints
Endpoint
Lorcaserin
Placebo
P value
Waist
circumference (cm)

−6.8
−3.9
<0.001
SBP/DBP (mm Hg)

−1.4 / −1.1
−0.8 / −0.6
0.04/0.01
Cholesterol (% Δ)
Total
LDL
HDL


−0.90
2.87
0.05
0.57
4.03
−0.21
0.001
0.049
0.72
Triglycerides (%)

−6.15
−0.14
<0.001
Safety
HR (beats/min)
Beck depression II

−2.0
−1.1
−1.6
−0.9
0.049
0.26
Intention-to-Treat Analysis with LOCF Imputation
Smith SR, et al. NEJM. 2010;363:245-256.
99
Randomized Placebo‐Controlled Clinical Trial
of Lorcaserin for Weight Loss in Type 2 DM
BLOOM‐DM Study - HbA1c
O’Neil PM, et al. Obesity (Silver Spring). 2012 Jul;20(7):1426-36.
Randomized Placebo‐Controlled Clinical Trial
of Lorcaserin for Weight Loss in Type 2 DM
BLOOM‐DM Study
Weight Loss
O’Neil PM, et al. Obesity (Silver Spring). 2012 Jul;20(7):1426-36.
101
Lorcaserin: Adverse Events Reported
by >5% in Any Group
Lorcaserin
(N = 3195)
Placebo
(N = 3185)
Headache
537 (16.8)
321 (10.1)
Dizziness
270 (8.5)
122 (3.8)
Nausea
264 (8.3)
170 (5.3)
Constipation
186 (5.8)
125 (3.9)
Fatigue
229 (7.2)
114 (3.6)
Dry mouth
169 (5.3)
74 (2.3)
N (%)
Intention-to-Treat Analysis with LOCF Imputation
Smith SR, et al. NEJM. 2010;363:245-256.
102
2011
Naltrexone SR/Bupropion
Naltrexone/Bupropion
• Mechanism of Action
–
–
Naltrexone ─ Opioid receptor antagonist
Bupropion ─ Dopamine/noradrenaline reuptake inhibitor
• Approved by FDA committee but FDA did not approve
until a CVD outcome study is performed due to
concerns about blood pressure and pulse in some
patients
• The Light Study (CVD outcomes) is under way;
estimated completion: July 2017
Apovian C, et al. Obesity. 2013.
Clinicaltrials.gov. Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese
Subjects With Cardiovascular Risk Factors (The Light Study). 2012. http://clinicaltrials.gov/show/NCT01601704
104
Mean Weight Loss
Naltrexone/ Bupropion
COR-I Phase 3
56 Weeks – Completer Population
Greenway FL, et al. Lancet 2010 Aug 21; 376:595. DOI:10.1016/S0140-6736(10)60888-4.
105
Naltrexone SR / Bupropion SR
Phase 3 Trial (COR-II)
A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II)
Apovian CM, Aronne L, et al. Obesity (Silver Spring). 2013 May;21(5):935-43.
106
Improvement in risk factors with use
of Naltrexone SR / Bupropion SR
Week 28
Measure
Placebo N = 456
Week 56
NB32 N = 825
P-value
Placebo N = 456
NB32 N = 702
108.6 ± 11.8
109.0 ± 11.8
−2.1 ± 0.5
−6.7 ± 0.3
112.8 ± 1.6
118.9 ± 1.6
−0.5% (−4.5%, +3.7%)
−9.8% (−12.4%, −7.1%)
51.6 ± 12.9
51.8 ± 13.6
−0.9 ± 0.5
+3.6 ± 0.4
116.8 ± 32.9
120.5 ± 30.2
−2.1 ± 1.3
−6.2 ± 0.9
94.2 ± 10.4
95.0 ± 11.3
−1.3 ± 0.6
−2.8 ± 0.5
10.7 ± 1.9
11.4 ± 1.9
+3.5% (−3.8%, +11.2%)
−11.4% (−15.9%, −6.6%)
P-value
Waist circumference, cm
Baseline
108.9 ± 11.7
109.3 ± 11.9
Change
−2.7 ± 0.4
−6.2 ± 0.3
113.4 ± 1.6
119.0 ± 1.6
−1.4% (−5.0%, +2.4%)
−7.3% (−9.8%, −4.8%)
Baseline
51.4 ± 13.1
51.4 ± 13.3
Change
−1.4 ± 0.4
+1.2 ± 0.3
Baseline
117.1 ± 32.6
119.8 ± 30.2
Change
0.0 ± 1.3
−4.4 ± 0.9
Baseline
94.2 ± 10.4
94.8 ± 11.2
Change
−1.7 ± 0.5
−2.1 ± 0.4
10.7 ± 1.9
11.4 ± 1.9
<0.001
<0.001
Triglycerides, mg/dL
Baseline
Percent change (95% CI)
0.007
<0.001
HDL-cholesterol, mg/dL
<0.001
<0.001
LDL-cholesterol, mg/dL
0.004
0.008
Fasting blood glucose, mg/dL
0.544
0.051
Fasting insulin, μIU/mL
Baseline
Percent change (95% CI)
−0.5% (−6.5%, +5.9%) −14.1% (−17.9%, −10.2%)
<0.001
<0.001
Systolic blood pressure, mm Hg
Baseline
118.2 ± 10.5
118.1 ± 10.0
Change
−1.2 ± 0.4
−0.9 ± 0.3
118.2 ± 10.5
117.9 ± 10.0
0.556
−0.5 ± 0.4
+0.6 ± 0.3
76.8 ± 7.0
76.7 ± 7.0
0.017
+0.3 ± 0.3
+0.4 ± 0.2
0.039
Diastolic blood pressure, mm Hg
Baseline
76.8 ± 7.0
76.8 ± 7.0
Change
−0.7 ± 0.3
+0.2 ± 0.2
Apovian CM, Aronne L, et al. Obesity (Silver Spring). 2013 May;21(5):935-43.
0.847
107
Side Effects
Naltrexone/Bupropion
Most frequent events:
– Nausea
• N=171 (29.8%) naltrexone 32 mg plus bupropion
• N=155 (27.2%) naltrexone 16 mg plus bupropion
• N=30 (5.3%) placebo
– Headache, constipation, dizziness, vomiting, and
dry mouth were also more frequent in the
naltrexone plus bupropion groups vs. placebo
– Transient increase of ~1·5 mm Hg in mean systolic
and diastolic blood pressure was followed by a
reduction of around 1 mm Hg below baseline in the
naltrexone plus bupropion groups
– Combination treatment was not associated with
increased depression or suicides vs. placebo
Greenway FL, et al. Lancet. 2010 Aug 21;376(9741):595-605.PMID: 20673995.
108
2010
Liraglutide
Liraglutide
• Glucagon-Like Peptide 1 (GLP-1) receptor agonist
approved in 2010 for treatment of type 2 diabetes
(1.8 mg/day)
• Appetite effect mediated by both the activation of
GLP-1 receptors expressed on vagal afferents and
hypothalamus
• Affects visceral fat adiposity, appetite, food
preference, and cardiovascular biomarkers in
patients with type 2 diabetes
• Suppresses appetite, and delays gastric emptying
• Phase III trials assessing effects of doses as high as
3.0 mg/day submitted to FDA
110
Effects of Liraglutide and Orlistat on Body
Weight in Nondiabetic Obese Adults
Astrup A, et al. Lancet. 2009 Nov 7;374(9701):1606-16.
Data are mean (95% CI) for the ITT population
111
Liraglutide Weight Loss: One Year
Supplementary Information Table 3: Mean changes in body weight
Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.
112
Liraglutide Weight Loss: Two Years
Liraglutide 3.0 mg for 1 year (and then maintained on 2.4/3.0 mg for the second year)
maintained a mean weight loss of 10.3±7.1 kg from screening over 2 years
3.0 mg
10.3±7.1 kg
weight loss
Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.
113
Liraglutide: Adverse Events
• Generally well tolerated and improved quality of life
• Adverse events mostly mild or moderate
• Gastrointestinal events (particularly nausea and
vomiting), consistent with the known physiological
effects of GLP-1, were more frequent than with
placebo
• At year 1, nausea and/or vomiting was associated
with greater weight loss with liraglutide 3.0 mg, but
even those who did not experience these events lost
more weight than those on placebo or orlistat
• Injection regimen did not impair adherence or cause
significant withdrawal during treatment or run-in
Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.
114
Obesity Drugs in the Pipeline
Beloranib
Beloranib: Phase 1 Trial Results – 4 weeks
Fumagillin-class methionine
aminopetidase-2 (MetAP2) inhibitor
Dosage
Placebo
0.1 mg/m2 (n=7)
0.3 mg/m2 (n=6)
0.9 mg/m2 (n=8)
Weight Loss
(kg)
-0.6 kg
•
N=19 obese women
•
Mean BMI 38 kg/m2
•
Dosage at 0.9 mg/m2 associated with
a 42% reduction in triglycerides 18%
reduction in LDL-cholesterol
(-4.5, -0.1)
-0.6 kg
(-4.5, -0.1)
–
-0.6 kg
(-4.5, -0.1)
•
Most frequent AE’s: headache,
infusion site injury, nausea, and
diarrhea
•
Nausea and infusion site injury
occurred more with beloranib vs
placebo
•
Loss of venous access most
common reason for discontinuation
-3.8 kg
(95% CI -5.1, -0.9)
No evidence of major tolerability or safety issues
(Phase 1 trials)
Improvement in C-reactive protein and
reduced sense of hunger
Hughes TE, et al. Obesity (Silver Spring). 2013 Mar 20. doi: 10.1002/oby.20356. [Epub ahead of print]
116
Beloranib: Phase 2 Trial
Interim Analysis - 12 Weeks
Fumagillin-class methionine
aminopetidase-2 (MetAP2) inhibitor
Dosage
Weight Loss
(kg)
Completers
n=19
Placebo (n=5)
+1.8 ±0.4
0.6 mg (n=5)
-3.8 ± 0.8
1.2 mg (n=6)
-6.1 ±1.5
2.4 mg (n=3)
-9.9 ± 2.3
•
Completers: n=19
•
Mean BMI 37.9 kg/m2
•
Administered through subcutaneous
injections 2x weekly over 12 weeks
•
Patients ate normally; not counseled
to change exercise habits
•
Beloranib-patients showed
improvements in cardiometabolic
risk factors including reduced
triglycerides, LDL cholesterol and
C-reactive protein (an inflammatory
marker) versus placebo
No evidence of major tolerability or safety issues
(Phase 1 trials)
ADA Poster Session 19-B Abstract #188-LB June 22, 2013
117
Anti-obesity
Medications in
Development
Kim GW, et al. Clin Pharmacol Ther. 2013 Oct 8. doi: 10.1038/clpt.2013.204. [Epub ahead of print]
118
Summary
•
•
•
•
Few choices of anti-obesity medications
Two new medications approved in 2012
Two more are pending approval
Medications can enhance weight loss for
select candidates and improve
cardiometabolic outcomes
• Medications are always only adjunct to diet
and exercise
• When we have more medications, we will
treat obesity more frequently.
119
New Perspectives and
Emerging Treatment Paradigms
Case Based Learning, Front-Line Practice
Strategies, and Real World Implementation of
Obesity Management in the Primary Care Setting
When, In Whom, Why, and How to Treat Obesity
Ken Fujioka, MD – Program Co-Chair
Director, Nutrition and Metabolic Research Center | Director, Center
for Weight Management | Scripps Clinic in San Diego, CA
Case Study 1
Metabolically Healthy Obese
►
43-year-old male accountant
●
6 feet tall, weight 225 pounds
●
Gained about 35 pounds after college (played
basketball in college)
●
Still plays recreational basketball and lifts weights
●
Wants to lose weight so he can dunk a basketball
●
And his much younger wife sent him in for his snoring
●
No known medical problems
Case Study 1
Physical Exam

BP: 124/72 Pulse 74
►
BMI = 30
►
Waist is 35 inches
►
ENT: normal
● Upper airway looks OK maybe a little narrowed
►
Skin normal
►
The rest of the exam is completely normal
►
What tests do you order?
Case Study 1 - Question 1
Which test is not needed in the work up
of the obese male ?
1) Comprehensive metabolic panel
2) Thyroid function
3) Overnight oximetry
4) Total testosterone
5) A1c
6) Lipids
7) Vitamin D level (25 OH)
Please Enter Your Response On Your Keypad
Case Study 1
The Basketball Player
►
Comprehensive metabolic panel
●
●
●
●
●
►
Completely normal
Fasting glucose 84
TSH 2.8 normal
Total testosterone 402
Lipids all with in normal parameters
Overnight oximetry : Sleep apnea work up
●
Normal
Case Study 1 - Question 2
Which lipid parameter has very little
improvement with weight loss?
1) Triglycerides
2) LDL
3) HDL
4) All lipid parameters are dramatically improved with
weight loss and made worse by obesity
Please Enter Your Response On Your Keypad
Case Study 1 - Question 3
Classify or stage the severity of this patient’s obesity:
1) Stage 0
2) Stage 1
3) Stage 2
4) Stage 3
5) Stage 4
Please Enter Your Response On Your Keypad
Case Study 1 - Question 4
What would be the best treatment option for this
patient?
1) Do nothing and reassure him he is healthy
2) Diet and lifestyle modification
3) Medications plus diet and lifestyle
4) Bariatric surgery
Please Enter Your Response On Your Keypad
Case Study 2
Hispanic Male
►
46-year-old Hispanic male born and raised in
Florida
►
Presents for his annual physical
●
Not good about getting an annual physical but
got moved up to a vice president job and needs
a physical for life insurance
►
BMI is 27
►
No history of medical problems
►
He has no complaints and feels great
Case Study 2
Hispanic Male
►
►
►
►
►
►
BMI 27
Waist 38 inches
Fasting blood sugar 104
A1c 5.9
Lipids
● TGs 289
● HDL 27
● LDL 109
The rest of his labs are all normal
Case Study 2 - Question 1
Does this patient meet the definition of obesity ?
1. No (not obese just overweight)
2. Yes (obese)
3. It depends on what which definition of obesity
you use (International vs. American)
4. It depends on what country you are in
Please Enter Your Response On Your Keypad
Case Study 2 - Question 2
Classify or Stage the severity of this patient’s obesity:
1) Stage 0
2) Stage 1
3) Stage 2
4) Stage 3
5) Stage 4
Please Enter Your Response On Your Keypad
Case Study 2 - Question 3
What would be the best treatment option for this
patient?
1) Do nothing and reassure him he is healthy
2) Diet and lifestyle modification
3) Medications plus diet and lifestyle
4) Bariatric surgery
Please Enter Your Response On Your Keypad
Case Study 2 - Question 4
Which medications would you consider ?
1) Metformin
2) Orlistat
3) Lorcaserin
4) Phentermine/Topiramate ER
5) Phentermine
Please Enter Your Response On Your Keypad
Case Study 3
►
37-year-old newly married Caucasian female
►
Has known polycystic ovarian syndrome
►
Told by her Ob-gyn to lose weight to improve her
chances of getting pregnant
►
The patient specifically asks for a “weight loss”
medication to kick start her weight loss
►
She also wants her thyroid tested and says a doctor in
the past gave her thyroid meds
Case Study 3
PCO Patient
►
BMI 34
►
Skin: acne scars with 6 inflammatory acne lesions on
the face
►
Hair: some lose on the scalp
►
Waist 44 inches
►
A1c 6.5
►
Fasting glucose 138
►
TSH is normal (1.8) and not on thyroid replacement
Case Study 3 - Question 1
Classify or stage the severity of this patient’s obesity:
1) Stage 0
2) Stage 1
3) Stage 2
4) Stage 3
5) Stage 4
Please Enter Your Response On Your Keypad
Case Study 3 - Question 2
Should you start thyroid replacement therapy?
1) Give her low dose replacement since she
was on it before
2) Her TSH is normal and she does not need
replacement
3) Give her low dose replacement as she will
need more thyroid hormone when she is
pregnant
Please Enter Your Response On Your Keypad
Case Study 3 - Question 3
What would be the best treatment option for this
patient?
1) Do nothing and reassure the patient she is healthy
2) Diet and lifestyle modification
3) Medications plus diet and lifestyle
4) Bariatric surgery
Please Enter Your Response On Your Keypad
Case Study 3 - Question 4
Which diabetic medications would you consider ?
1) Metformin
2) Sulfonylurea
3) DPP-4 inhibitor
4) GLP-1
5) SGLT-2 inhibitor
6) Pioglitazone
7) Insulin
Please Enter Your Response On Your Keypad
Case Study 3 - Question 5
Which weight loss medication would you consider ?
1) 1. Orlistat
2) 2. Phentermine
3) 3. Phentermine/topiramate ER
4) 4. Lorcaserin
Please Enter Your Response On Your Keypad
Case Study 4
►
55-year-old morbidly obese male
►
Had a myocardial infarction 8 months ago and is
finishing up cardiac rehab
►
No CHF and had a CABG with excellent results
►
Has bilateral degenerative joint disease and the
orthopedic surgeon will not operate until he loses
weight
►
Due to his weight and knees he now has trouble just
walking from room to room
● Can’t go up and down stairs
Case Study 4
Morbidly Obese Male
►
BMI 51
►
BP: 124/82 ; pulse 80
►
Very narrowed upper airway (pharynx)
►
+ 2 pitting edema of the lower legs
►
Mood is depressed
►
Everything else normal
►
Labs all normal (normal blood sugar)
►
Lipids very well controlled
Case Study 4 - Question 1
Patient is on the following medications:
which medication will make weight loss more difficult
1) HCTZ
2) ARB
3) Beta-blocker
4) Metformin
Please Enter Your Response On Your Keypad
Case Study 4 - Question 2
Classify or stage the severity of this patient’s obesity:
1) Stage 0
2) Stage 1
3) Stage 2
4) Stage 3
5) Stage 4
Please Enter Your Response On Your Keypad
Case Study 4 - Question 3
What would be the best treatment option for this
patient?
1) Do nothing and reassure him he is healthy
2) Diet and lifestyle modification
3) Medications plus diet and lifestyle
4) Bariatric surgery
Please Enter Your Response On Your Keypad
Case Study 5
►
48-year-old depressed female
►
Peri-menopausal
►
Wants to lose weight to feel better about herself
● “ I am depressed about being fat”
►
I follow a gluten free diet and exercise 1 to 2 hours a
day and can’t lose weight
►
It has to be my thyroid or some hormonal problem
Case Study 5
Obese Peri-menopausal Female
►
Medications: 30 mgs paroxetine
►
No health problems
►
BMI 32
►
Labs
●
●
●
TSH 1.3 (WNLs)
Lipids normal
Glucose normal
Case Study 5 - Question 1
Classify or stage the severity of this patient’s obesity
1) Stage 0
2) Stage 1
3) Stage 2
4) Stage 3
5) Stage 4
Please Enter Your Response On Your Keypad
Case Study 5 - Question 2
What would be the best treatment option for this
patient?
1) Do nothing and reassure her she is healthy
2) Diet and lifestyle modification
3) Medications plus diet and lifestyle
4) Bariatric surgery
Please Enter Your Response On Your Keypad
Case Study 5 - Question 3
Which medication changes would you consider ?
1) Wean off paroxetine
2) Start bupropion
3) Orlistat
4) Lorcaserin
5) Phentermine/topiramate ER
6) Phentermine
Please Enter Your Response On Your Keypad
Case Study 6
►
A 49-year-old female with severe obesity presents for
assistance with weight loss
●
T2DM x 4 years
• Metformin 500 mg BID, liraglutide 1.8 mg sc q d
●
Hypertension
• Losartan 100 mg q d, diltiazem 360, chlorthalidone 50 mg q d
●
Hyperlipidemia
• Simvastatin 20 mg q d
●
GERD
• Lansoprazole 30 mg q d
●
●
OSA – nightly CPAP
Arthralgias of knees
Case Study 6
►
Weight history
●
●
●
►
Overweight since high school followed by progressive,
ratcheting weight gain since entering the work force to
highest weight of 340 lbs.
Attributes obesity to work and family stress, and
providing care to family members
Previously participated in commercial programs (Jenny
Craig and Weight Watchers) and saw RD when she was
diagnosed with T2DM
Social history
●
Single, living with brother and Labrador retriever
‘Bear’, works as quality assurance analyst for BCBS
Case Study 6
►
Diet history
●
►
Skips breakfast, first meal at 11:00 AM is left-overs
or fast food. Second meal is 6:30 PM, either fast
food or easy prep foods [although appetite
reduced since starting on liraglutide, selection of
foods and portions have not changed].
Physical activity history
• Limited to ADLs. Has stationary bike and treadmill
in home but seldom used
Case Study 6
►
Examination
●
●
●
●
►
Weight 352 lbs, height 66.25 in, BMI 52.1 kg/m2
BP 128/62, HR 92
Heart – Grade 2/6 SEM
Extremities – dystrophic skin changes, 1+ edema
Labs
●
●
●
Glucose 95 mg/dl, HbA1c 6.5%
BUN 19 mg/dl, eGFR 73 ml/min/1.73
TC 152 mg/dl, LDLc 70 mg/dl, HDLc 46, TG 181 mg/dl
Case Study 6 - Question 1
What would you recommend regarding weight
management?
1)
2)
3)
4)
5)
Refer to commercial program
Refer to registered dietitian
Initiate lifestyle counseling yourself
One of the above + pharmacotherapy
Refer for bariatric surgery
Please Enter Your Response On Your Keypad
Case Study 6
RD Visit
►
Further assessment
●
●
●
►
Brother does the grocery shopping – will not buy
healthier foods since he believes it is too expensive
Eats out often, choosing fast foods
Eats out of boredom and anxiety
Counseling
●
●
●
●
Make small changes, do not skip breakfast
Track diet [patient response “is not going to happen”]
Healthy ‘budget conscious’ items
Snack and meal ideas
Case Study 6
Follow Up at 7 Weeks
►
Implemented some changes from RD visit: not
skipping meals, less ‘junk food’
►
6 lbs. weight loss initially, no change in past 3
weeks.
►
Went to bariatric surgery seminar at my request
but considers surgery a ‘mutilation’ and is not
interested
►
Perceives lifestyle changes to be very hard.
Difficult of focus on self-care and is feeling
pessimistic
Weight Graph from EHR
Case Study 6 - Question 2
What would your approach be at this time?
1) Stay the course and reinforce importance of
adherence
2) Refer to mental health professional
3) Prescribe a very-low-calorie diet (VLCD) to reduce
caloric intake further
4) Emphasize need to start an exercise program
5) Initiate pharmacotherapy
6) Revisit her negative view of bariatric surgery
Please Enter Your Response On Your Keypad
Rationale for Prescribing
Anti-Obesity Medications
►
Weight loss, and maintenance of lost
weight, is difficult for many patients
►
The primary function of anti-obesity
medication is to assist with weight loss and
maintenance of lost weight by reducing
hunger and/or increasing satiety, thus
allowing patients to follow a caloriereduced diet with more resolve
*an anti-obesity medication may have independent effects, e.g., orlistat on LDLc,
liraglutide on glucose
Case Study 6
Follow Up
►
The addition of pharmacotherapy was
discussed and patient’s attitudes assessed.
►
Use and side effects of
phentermine/topiramate ER were discussed
and asked her to review the company website
[lorcaserin was not available at the time]
►
Patient elected to try medication and a
prescription was provided
Weight Graph from EHR
46 lbs = 14%
Case Study 6
Biomarkers
Baseline
3
months
7
months
10
months
14
months
325.2
303.5
(6.6%)
290
(10.7%)
282
(13.2%)
280
(13.8%)
Glucose, mg/dl
95
93
89
85
88
HbA1c, %
6.5
6.3
6.0
5.9
6.0
TC, mg/dl
182
175
183
176
175
LDL-c, mg/dl
110
103
107
105
104
HDL-c. mg/dl
46
45
51
54
51
TG, mg/dl
181
135
127
83
98
Value
Weight, lbs,
(% wt loss)
New Perspectives and Emerging Treatment Paradigms
for Individualizing Obesity Management
Optimizing Weight Loss in the Primary Care
Setting: Where Are We Now, and Where Are
We Going?
Lee M. Kaplan, MD, PhD
Obesity, Metabolism & Nutrition Institute
Massachusetts General Hospital
Harvard Medical School
LMKaplan@partners.org
April 11, 2014
What is Obesity?
Excessive fat accumulation
that presents a risk to health
• The presence and severity of obesity can be
estimated by a variety of biomarkers
•
•
•
•
•
Body mass index (BMI)
Body composition
Body fat distribution
Risk scores
Comorbidities
• But these markers should not define obesity
Why Obesity is NOT a Disease
• It is a lifestyle choice
• No specific symptoms associated with it
• It is a risk factor for disease, not a disease itself*
•
Calling it a disease would define one-third of Americans
as being ill and could lead to more reliance on costly
drugs and surgery rather than lifestyle changes
•
Some people might be overtreated because their BMI
was above a line designating them as having a disease,
even though they were healthy
* What about high cholesterol or hypertension?
Why Obesity IS a Disease
• It is associated with impaired body function
• Like other diseases, it results from physiological
dysfunction (precipitated by numerous forces in
modern society)
• It causes, exacerbates or accelerates more than 65
significant comorbid diseases
• It is associated with a substantial burden of morbidity
and premature death
Obesity Complications – Targets of Therapy
•
•
•
•
•
•
•
•
•
•
Diabetes
Hypertension
Hyperlipidemia
Fatty liver disease
Sleep apnea
GERD
Arthritis
Inflammatory and autoimmune diseases
Cancer (12 types)
Cognitive dysfunction
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
Core Principle of Obesity Treatment
There is broad variability in the weight loss
response to ALL therapies for obesity
• Lifestyle interventions
• Medications
• Surgery
Weight Loss Variability after Gastric Bypass
Bessler et al., 2008
Weight Loss Variability after Gastric Banding
Bessler et al., 2008
Weight Loss Variability with Sibutramine
Sibutramine-induced Weight Loss
Responder Tail
Adapted from Hansen DL et al., IJO 2001; 25:496
Weight Loss Variability with Lorcaserin
% of Patients
Lorcaserin-induced Weight Loss
% Weight Loss
Weight Loss Variability on Different Diets
Zone Diet
Weight Change
Weight Change
LEARN Program
Ornish Diet
Weight Change
Weight Change
No. of Subjects
No. of Subjects
Atkins Diet
Adapted from Gardner et al, JAMA 2007
Wide variability in therapeutic response
is best explained by clinically important
subtypes
The Obesities – A Plethora of Discrete Disorders
Leptin deficiency
LepR deficiency
MC4R deficiency
MSH deficiency
Sim-1 deficiency
PC-1 deficiency
KSR2 deficiency
MRAP2 deficiency
SH2B1 deficiency
BDNF deficiency
trkB deficiency
Carpenter syndrome
Cohen syndrome
Ayazi syndrome
MOMO syndrome
Rubenstein-Taybi
syndrome
Fragile X syndrome
BFL syndrome
Albright osteodystrophy
Prader- Willi syndrome
Bardet-Biedl syndrome
Alström syndrome
Hypothalamic
Hyperphagic
Thermogenesis deficient
Circadian-disrupted
Stress-induced
Central
Peripheral
Diffuse
Neonatal
Early childhood
Peripubertal
Gestational
Menopausal
“Healthy”
Metabolic
Inflammatory
Diet-dependent
Exercise-sensitive
Sleep-sensitive
Insulin-induced
Steroid-induced
Progesterone-induced
Psychotropic-induced
Antibiotic-induced
Endocrine disruptor
Phentermine-responsive
Lorcaserin-responsive
Topiramate-responsive
Metformin-responsive
Bupropion-responsive
GLP-1 responsive
Bypass-responsive
Bypass-resistant
Gastric band-responsive
Multiple Subtypes = Variation in Treatment Response
What Differs Among Different Obesity Subtypes
•
•
•
•
Timing of obesity onset
Fat location and distribution
Metabolic consequences
Phenotypic differences
•
•
•
•
Hunger
Satiety
Reward-based eating
Energy expenditure
• Response to environmental causes
• Eating
•
•
•
•
Exercise
Stress
Sleep deprivation
Circadian disruption
• Response to therapies
Number of Subjects
Heterogeneity of Response
Highly
responsive
subgroup
0
Weight Loss
Conclusions
• Obesity IS a disease, regardless of its designation
• There are implications (to all of us) of thinking about it this way
•
•
•
•
Physiologically based therapies
Heterogeneity of cause
Variable treatment response
Opportunity to benefit selected subpopulations – value of predictive markers
• Attitudes about obesity underlie the major barriers to its treatment
• Education and (evidence-based) participation by all stakeholders is the
key to ultimate success
Take-home Messages
Obesity Treatment
•
Lifestyle adjustment is the mainstay of therapy
•
Medications can be effective
•
In selected patients
• Medications work differently in different patients – requires ‘trial
and error’ approach
•
Combination therapies look particularly promising
Practical Guidance
Go Slow and Try Different Approaches
• Test therapies sequentially
• Pursue combination therapies – including combinations of specific
lifestyle changes with more classical medical approaches
• Be supportive
•
•
Be persistent
Be there for the patient
Aim for “cure,” but always provide care.
Why is all this so important?
• The current standard of care for obesity is:
0
• For ultimate success, this needs to change
• Ignoring obesity needs to become no more acceptable
than ignoring other disorders
• There needs to be incentive to embrace obesity
treatment
A Call to Action
 Determine BMI at each visit
 Counsel patients with obesity on the risks of excess weight and the
benefits of weight loss
 Identify the medical comorbidities of obesity in each patient
 Pursue a step-wise strategy for weight loss – lifestyle, medications and
surgery as needed
 Help patients maintain weight loss by optimizing the patients lifestyle –
healthy diet, regular exercise, adequate sleep, stress reduction
184
Question 1
Why is weight regain after dieting so common?
1. Exercise, not diet, is the most effective means of losing weight
2. The body reacts to weight loss by decreasing daily energy
expenditure
3. Diet foods are boring and patients stop eating them
4. Dieting increases the body’s set point for fat mass
5. Weight loss often leads to unwanted effects that cause
patients to sabotage their efforts
Please Enter Your Response On Your Keypad
Question 2
Which of the following is NOT a demonstrated
benefit of modest regular exercise?
1. Enhances weight loss effect of other lifestyle
changes
2. Causes weight loss directly
3. Alters appetite to favor healthier foods
4. Stimulates fat to burn more calories
5. Decreases cardiovascular risk
Please Enter Your Response On Your Keypad
Question 3
Which of the following comorbidities of
obesity has NOT been shown to improve with
modest (5-10%) weight loss?
1. Type 2 diabetes
2. Hypertension
3. Dyslipidemia
4. Cardiovascular risk
5. Fatty liver disease
Please Enter Your Response On Your Keypad
Question 4
If a patient with prediabetes and obesity maintains a
4% weight loss over 4 years, how much do they lower
their risk of developing diabetes?
1. <10%
2. ~25%
3. ~50%
4. ~75%
5. >90%
Please Enter Your Response On Your Keypad
Question 5
Which of the following medications is NOT currently
approved by the FDA for the treatment of obesity?
1. Orlistat
2. Liraglutide
3. Phentermine
4. Lorcaserin
5. Phentermine / Topiramate ER combination
Please Enter Your Response On Your Keypad
Question 6
Which of the following weight loss
medications do NOT work through central
nervous system mechanisms?
1. Bupropion
2. Lorcaserin
3. Liraglutide
4. Topiramate ER
5. Phentermine
Please Enter Your Response On Your Keypad
Question 7
Which of the following is NOT a primary
mechanism of weight loss from centrallyacting weight loss medications?
1. Change in food preferences
2. Decrease in appetite
3. Increase in resting and post-meal energy expenditure
4. Demonstrating the value of a healthier weight to the patient
5. Lower physiologically defended body weight
Please Enter Your Response On Your Keypad