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
KEN FUJIOKA, MD - PROGRAM CHAIRMAN
Director, Nutrition and Metabolic Research Center
Director, Center for Weight Management
Scripps Clinic
San Diego, CA
LAWRENCE J. CHESKIN, MD, FACP, FTOS
Associate Professor
Johns Hopkins Bloomberg School of Public Health
Director, Johns Hopkins Weight Management Center
Johns Hopkins Hospital
Baltimore, MD
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
New Perspectives and Emerging Treatment
Paradigms for Obesity Management
Current Challenges and Barriers to
Obesity Treatment in the
Primary Care Setting
Ken Fujioka, MD – Program 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
2015
►
Medications approved in 2013
●
●
►
Lorcaserin
Phentermine/Topiramate ER
Medications approve over the last few
months (end of 2014)
●
●
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
• Bupropion/Naltrexone 5% at 16 week
• Liraglutide 3 mgs 4% at 16 weeks
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
Recommended to check a pregnancy test
before starting and monthly
Bariatric Surgery
►
Bariatric surgery
●
Sleeve gastrectomy comes of age
• Procedure between an adjustable band and gastric
bypass
• Excellent weight loss: weight loss between an
adjustable band and a gastric bypass
• 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%)
Seeing more weight loss medications coming down in
price for cash patients
Bariatric surgery
●
Vast majority of insurances cover
New Perspectives and Emerging Treatment
Paradigms for Obesity Management
Screen and Intervene:
A Call-to-Action to Treat Obesity
Who Should We Treat For Obesity and Why?
What Represents a Successful Outcome?
How Should We Measure Results
What Are Our Goals?
Lawrence J. Cheskin, MD, FACP, FTOS
Director, Johns Hopkins Weight Management Center
Associate Professor, Health, Behavior & Society
Joint Appt: Medicine (GI); International Health (Nutrition)
Obesity Trends* Among US Adults
BRFSS, 1990, 1999, 2008
*BMI 30, or
about 30 lbs
overweight for
5’4” person
BRFSS=Behavioral Risk Factor Surveillance System
Severe and Morbid Obesity Is Increasing
More Rapidly Than Mild Obesity
Increased Prevalence Between
NHANES 2 & 3 (%)
100
80
60
40
20
0
≥25
≥27
≥30
Body Mass Index (BMI)
Normal: 18.5-24.9
Class 1 Obesity: 25-29.9 (overweight)
Class 2 Obesity: 30.0-39.9 (severe)
Class 3 Obesity: 40 or more (morbid/extreme)
Sturm, R. Public Health. 2007. July;121(7):492-496.
≥40
Prevalence of Extreme (Morbid) Obesity
(BMI ≥40) by Gender and Ethnicity
Women
16
14
12
10
8
6
4
7%
4.4%
4%
2
0
White
Men
Black
Men
Flegal KM, et al. JAMA. 2010;303:235-241.
Mexican
Men
Prevalence of Extreme Obesity (%)
Prevalence of Extreme Obesity (%)
Men
16
14.2%
14
12
10
8
6.7%
6.4%
6
4
2
0
White
Women
Black
Women
Mexican
Women
Children and Obesity
Approximately 25% of children and
adolescents are overweight
►
More than any other known time in history
►
Life expectancy
may decline
as a result
Life Expectancy and Obesity
►
Two 2009 meta-analyses determined:
1. 30-35 kg/m2, median survival is reduced
by 2-4 years
2. 40-45 kg/m2 medium survival is reduced
by 8-10 years
Prospective Studies Collaboration. Lancet. 2009;373(9669):1083-1096.
Peeters A, et al. Ann Intern Med. 2003;138:24-32.
Mason J, et al. JAMA. 2003;289:229-230.
How Might Obesity Shorten Lifespan?
Leading Causes of Death, U.S.
Cause of Death
Rate/100,000
Obesity Related?
CHD
175
Yes
Cancer
133
Yes
Accidents
35
No
Stroke
31
Yes
COPD
19
No
Diabetes
16
Yes
Comorbid Conditions
and BMI>27 kg/m2
Common comorbid
conditions in obesity
►Hypertension
►Dyslipidemias
►Type
No Comorbidity 35%
Comorbidity 65%
Anderson JW, et al. Obes Res. 2001;9:S326-S334.
2 diabetes
BMI and Relative Risk
of Type 2 Diabetes
70
Relative Risk
60
50
40
30
20
10
0
<22
22-22.9 23-23.9
24-24.9
25-26.9 27-28.9 29-30.9 31-32.9
BMI
Adapted from Willett WC, et al. N Engl J Med. 1999;341:427-434.
33-34.9
35+
Intentional Weight Loss (< 20 lbs) and
Predicted Reduction in Mortality
Source: Williamson, D.F, et al. (1995). Am J Epidemiol 141: 1128–1141
Medical Complications of Obesity
Stroke
Pulmonary disease
• Abnormal function
• Obstructive sleep apnea
• Hypoventilation syndrome
Pancreatitis
Nonalcoholic fatty
liver disease
• Steatosis
• Steatohepatitis
• Cirrhosis
Idiopathic intracranial
hypertension
Cataracts
Coronary heart disease
Diabetes
Dyslipidemia
Hypertension
Gynecologic abnormalities
Gall bladder disease
• Abnormal menses
• Infertility
• Polycystic ovarian syndrome
Cancer
• Breast
• Uterus
• Cervix
• Prostate
• Kidney
• Colon
• Esophagus
• Pancreas
• Liver
Osteoarthritis
Skin
Gout
Phlebitis
• Venous
• Stasis
Costs of Obesity
►
Obesity and inactivity are estimated to cause
300,000- 400,000 US deaths annually
► Overtaking smoking as the #1 preventable cause of
death
► Annual direct and indirect costs are ~ $147 billion
(2008)
► Plus cost of diet products and programs: ~$50
billion (2006)
► Obesity-attributable direct medical expenditures
are estimated at $75 billion ($17 billion financed by
Medicare, $21 billion Medicaid)*
► This represents >10% of all US health care costs
Costs ($)*
Effect of Obesity on Lifetime Medical Care
Costs* in Men (~Same as Women)
Age (y)
55-64
45-54
35-44
37.5
Up
100%
32.5
27.5
2
BMI (kg/m )
Up
Up
50%
20%
22.5
*Total cost of CHD, type 2 DM, hypertension, hypercholesterolemia, stroke
Thompson et al. Arch Intern Med 1999;159:2177.
A Classification of the Obesities
Neuroendocrine Obesities
►
►
►
►
►
►
►
►
Hypothyroidism
Hypothalmic syndrome
Cushing’s syndrome
Polycystic ovary (Stein-Leventhal)
syndrome
Pseudohypoparathyroidism
Hypogonadism
Growth hormone deficiency
Insulinoma and hyperinsulinism
Nutritional Imbalance and Obesity
►
►
High-calorie, high-fat diets
Cafeteria diets
Physical Inactivity
►
►
►
Enforced (postoperative)
Aging
Job-related
Genetic (Dysmorphic) Obesities
Iatrogenic
►
►
Drugs (psychotropics, corticosteroids)
Hypothalamatic surgery
►
►
►
Autosomal recessive
X-linked
Chromosomal
Drugs Associated with
Weight Gain
►
Steroids; BCPs; HRT
►
Tricyclic antidepressants
►
Phenothiazines
►
Lithium
►
Antihistamines
►
Sulfonylureas, insulin
►
Beta blockers, thiazides
Regulation of Body Weight
Calories consumed in 1 year:
980,000
Weight gained / year* (kcals fat): 1/2 lb (1,700)
Energy balance Error =
0.17%
*Average over 20 yrs (30-50 yrs of age, Framingham study)
Portion Size and Consumption

Portion sizes began growing in the 1970s

Marketplace portions are now 2-8x standard serving
sizes

In children, (~ to adults), doubling portions of a lunch
entrée increased entrée and total energy intakes by
25% and 15% (Orlet et al. 2003). When children were
allowed to serve themselves, they consumed 25%
less of the entrée than when served a large entrée
portion.
Diet Composition and Satiety
Hierarchy of satiety (per kcal):
Protein
Complex carbohydrates
Simple carbohydrates
Fat (unsaturated > saturated)
Ethanol
Ethanol may even stimulate further food intake
Liquids are less satiating than solids
Obesity and Macronutrients
►
Obese prefer fattier & sweeter foods
more than lean
►
“Passive” over consumption of calories
may occur on high fat diets
►
Prevalence of obesity in populations
correlates with % dietary energy from fat
►
Some evidence for genetically-influenced
ease of wt gain on high fat diet
Nibbling Versus Gorging
►
Obese individuals frequently eat fewer meals per
day
►
Of 379 men fed 1–2 meals per day, they were
heavier, had higher cholesterol, and higher glucose
than those who ate more frequently
►
School children fed three meals per day gain more
than those fed five to seven meals per day
The Other Side of the
Energy Balance Equation
Is being sedentary a risk factor for obesity?
►
Few historical records of activity levels.
►
In USA: inverse correlation between self-reported
P-act and BMI
●
True for men, women, AA, Latino, white, etc.
Obesity and Types of P-act
►
Moderate intensity exercise burns more fat than
high, but high intensity exercisers have the lowest
BMIs
►
Both aerobic and resistance exercise are helpful in
weight control
►
Short bouts of exercise (3x10min) are as effective
for wt loss as long (1x30min) if total EEact is equal
(Jakicic)
Obesity and Exercise
►
It is much more effective to eat less than to try to
burn off the caloric equivalent
●
Running a marathon burns about 2600 kcal or the
equivalent of 2/3 of a lb. of body fat
►
Exercise plays a key role in maintenance of
weight loss
►
Promotes preferential loss of fat stores
►
May ameliorate obesity-related conditions
Types of Physical Activity
►
Incidental and fidgeting (Non-exercise activity
thermogenesis, NEAT)
►
Lifestyle change
►
Progressive walking
►
Traditional exercise
●
●
►
Aerobic dance
Strength training
Sports
WHY DO I EAT—LET ME COUNT THE WAYS
The concept of appropriate/inappropriate eating cues
Food as a habit
Food as a stress reliever
Food as a reward
Food as a boredom reliever
Food as a social facilitator
Food as love
Food as a mountain
Assessing Obesity in Clinical Practice
Whom should we treat and why?
Body-mass index (BMI) = weight (kg)/height (m)2
●
●
●
●
Normal weight: BMI 18.5-24.9
Overweight: BMI 25.0–29.9
Obesity: BMI 30.0-39.9
Severe obesity: BMI 40.0+
BMI is positively correlated with health risk
Source: NHLBI Obesity Guidelines. Obesity Res 6(suppl 2) (1998)
Continued
Those at Highest Risk
Waist circumference modifies the risk at any given BMI
High risk:
• Men > 40 inches
• Women > 35 inches
►
Indirect measure of central adiposity, correlated with visceral fat
►
Excess fat in the abdomen is an independent predictor of risk
factors and morbidity
Use a tape measure around widest point above umbilicus
►
Source: NHLBI Obesity Guidelines. Obesity Res 6(suppl 2) (1998)
What Does our Toolkit Offer for Obesity?
►
Lifestyle modification
●
●
●
Diet
Physical activity
Behavior modification
►
Pharmacotherapy
►
Surgery
Goals of Treatment
►
FDA criteria for successful /medically significant
weight loss includes:
5% or > weight loss
Note: patients are rarely satisfied with 5%;
may have unrealistic expectations
Medically Significant Indeed…
When can we get patients off medications?
►
Hypertension:
 At 5, 10, and 15% weight loss: 3, 39, and 39% of the patients achieved
at least 1 discontinuation of an antihypertensive
Cardiorenal Med 2013;3:17–25
►
High cholesterol:
 55% stopped taking “statin” medication
And achieved normal cholesterol & TG values
►
Type-2 diabetes:
 44% stopped medications, including insulin and oral agents with
improvements in fasting blood glucose / HbA1c
• The initial effect often occurs quite early during wt loss
• 11% wt loss mean needed to D/C insulin; 7-14% oral agents
PLoS ONE 7(2): e32395. doi:10.1371/journal.pone.0032395
Weight Loss % vs. Probability of Dose
Reductions of HTN meds
Cardiorenal Med 2013;3:17–25
However, Lifestyle Modifications Alone
May Not Provide Long-Term Results
►
Diet alone
●
●
►
Diet and behavior modification
●
●
►
75% regain most of their weight by year one
85%–90% regain most of their weight by year two
71% regain within 30 months
Weight regain greater than initial weight by year five
Diet and behavior modification with exercise
●
58% regain weight lost by year two
All Diets are Alike?
► Evidence
from recent studies
suggests that diet type is irrelevant:
each diet induces some weight loss
and some weight maintenance
Bottom Line….
►
The jury is still out on just important diet
composition is for weight loss and maintenance
►
However, at least over the shorter-term, there is
substantial evidence that different diets vary in the
ease of adherence, and satiety they provide
►
High protein, high fiber, lower energy density foods
are more satiating physiologically
►
High protein also takes advantage of the thermic
effect of food component of resting metabolic rate
►
Be guided by your experience and the preferences of
the patient to select diet plans
Pharmacotherapy for Obesity
On the Menu Currently
►
Comparing drug with placebo for 26+ weeks:
●
●




Mean weight loss on phentermine = 8.1 percent (17.4 lbs >
placebo)
Mean weight loss on orlistat: 3.4 percent (7.5 lbs > pl)
Qsymia trials: Mean weight loss of >10%
Belviq/lorcaserin trials: Mean wt loss of 3.5-5%
Contrave trials up to 10%
Liraglutide trials mean 7%
►
Fewer than 3% of obese are Rx’d; low refill rates
►
7500 practitioners write 50% of all weight loss scripts
Mean Effectiveness of Non Pharmacologic and
Pharmacologic Weight Loss Approaches
Franz MJ, et al. J Amer Diet Assoc. 2007;107:1755-1767.
Principles of Obesity Medication Use
►
Recommended goal = 10% in 6 months
►
Lifestyle interventions are the foundation of medicating for obesity
►
The behavioral approach should be implemented with knowledge of the
medication’s mechanism of action
►
Obesity medications do not cure obesity, just as anti-hypertensives do not cure
hypertension
►
Not all patients respond to a weight loss medication
●
►
If the drug’s use is not associated with weight loss within four weeks,
it should be stopped
Medications work as long as they are used
●
●
Weight gain occurs on stopping medications, although there is some
evidence in support of efficacy of intermittent medication
Regain tends to occur gradually even with continued use: cycle them?
Adapted from: National Institutes of Health. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and
Obesity in Adults: The Evidence Report. National Institute of Health; NHLBI. NIH Pub No. 00-4084, 2000.
Bariatric Surgery for the
Treatment of Obesity
Weight Loss
(% of Excess Weight)
0
20
40
60
80
100
0
BMI (kg/m2): 50
2
4
6
8
10
12
Years
After Surgery
34
35
•Insurance-covered,
unlike most medical treatments
•Rapid growth in cases performed
•Better
statistics on weigh maintenance than medical Rx
14
35
Bariatric Surgery
Indications
1. BMI >40 kg/m2 OR…
BMI 35–39.9 kg/m2 PLUS:
life-threatening cardiopulmonary disease, severe
diabetes, or
major lifestyle impairment
2. PLUS: Failure to achieve adequate weight loss
with nonsurgical treatment
NIH Consensus Development Panel. Ann Intern Med 1991;115:956.
Surgical Weight Loss Procedures
LAGB
Laparoscopic
Adjustable
Gastric
Banding
LRYGB
Laparoscopic Rouxen-Y
Gastric
Bypass
GS
Gastric
Sleeve
BPD
Biliopancreatic
Diversion
Potential Complications
of Surgical Weight Loss
►
Mortality rate after discharge – possibly
due to pulmonary emboli or arrhythmias
(not yet certain)
►
Acute complications
●
►
Hemorrhage, leaks, bowel obstruction, infection, blood
clots
Long-term complications
●
●
●
●
●
Nutritional deficiency: Fe and B vitamin
Neuropathies; especially from thiamine deficiency
Internal hernias
Gallstones
Nausea
Pories,W. The Journal of Clinical Endocrinology and Metabolism. Vol 93, No.11 s89-s96. 2008
Introduction To:
The Johns Hopkins
Weight Management Center
www.jhsph.edu/weight
(p) 410-502-0145
(f) 410-502-6719
www.jhsph.edu/weight
JHWMC Program
►
Multi-disciplinary
►
Physician supervised
►
Individualized plans
►
Meal replacements / food-based / combination
►
Comprehensive assessments
►
Weekly groups or individual follow-up
►
Transition to long-term maintenance
Physician / Medical Monitoring
►
Health history / physical exam
►
Recent blood test / ECG review
►
Contact with referring physician
►
Appetite medications if needed
►
Monitoring of safety during diet
►
Adjustment of medications for
BP, cholesterol, diabetes, etc.
Exercise Physiologist
►
Metabolic assessment
►
Body composition assessment
►
Exercise Rx
►
Personal training
►
Motivation
Registered Dietitian
►
Nutrition assessment
►
Meal planning
►
Dietary coaching
►
Dining out guidance
►
Recipes
Behavior Therapist
►
Psychological assessment
►
Trigger identification / modification
►
Coping strategies
►
Individual psychotherapy
►
Motivation
Results - Data
►
Chart Review of 85 recent participants
●
►
Avg. starting weight:
●
►
222 lbs (BMI of 34.0)
Avg. weight loss:
●
►
260 lbs (BMI of 40.5)
Avg. weight upon completion:
●
►
(58 women, 27 men)
38 lbs (range 2 - 232 lbs)
Avg. rate of weight loss:
●
2.0 lbs/wk (range 0.1-6.0 lbs/wk)
As a Result of Weight Loss…
►
Hypertension ↓
►
High cholesterol ↓
►
Type-2 diabetes ↓
.
As a Result of Weight Loss…
►
Decreased need for medications or treatment for:
● Arthritis / pain control
● Gastroesophageal reflux disease (GERD)
● Obstructive sleep apnea (off CPAP)
● Angina pectoris
● Non-alcoholic fatty liver disease (NAFLD)
Other Common Outcomes
►
Lower cost of health care
►
Improved Health-Related Quality of Life
►
Improved mood & self-esteem
►
Improved fertility
►
Better sleep
►
More energy/decreased fatigue
.
In summary, treating obesity ain’t easy,
but is worth working hard at…
So what’s our best hope? Obesity Prevention!
►
Change the food supply: availability, cost,
advertising, energy density
►
Change the built environment: paths, safety
►
Change our schools
►
Change attitudes and beliefs
►
Serve as role models ourselves
►
Devote resources to research, programs,
reimbursement
►
Be persistent, and good luck!!
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
Lawrence J. Cheskin, MD, FACP, FTOS
Director, Johns Hopkins Weight Management Center
Associate Professor, Health, Behavior & Society
Joint Appt: Medicine (GI); International Health (Nutrition)
Obesity Management Case Study #1
• 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
Examination and Laboratory Results
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
Weight and Lifestyle History
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
Obesity Management Case Study
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 cognitive-behavior
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
Clinical Progress
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%)
Obesity Management Case Study
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
Obesity Management Case Study
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.
Obesity Management Case Study
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
Clinical Progress
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%
Obesity Management Case Study
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
Clinical Progress
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)
Obesity Management Case Study
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 lowcalorie (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
Clinical Progress
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%)
Weight Loss Summary
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
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
Slide:Dr.
Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics (2010) 87 6, 652–662. doi:10.1038/clpt.2010.57
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
Hypothalamic
La
Lesions
Other Circuits Enhancing or Inhibiting Food Reinforcement
these must be considered in treating obesity
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
Slide:Dr.
Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics (2010) 87 6, 652–662. doi:10.1038/clpt.2010.57
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%
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
Case Study 2
Hispanic Male
►
46-year-old Hispanic male born and raised in Los
Angeles
►
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) Lorcaserin
3) Phentermine/Topiramate ER
4) Bupropion/Naltrexone
5) Liraglutide 3.0 mgs
Please Enter Your Response On Your Keypad
Obesity Management
Case Study 3
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 (she is not pregnant now)
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) Orlistat
2) Phentermine
3) Phentermine/topiramate ER
4) Lorcaserin
5) Naltrexone /Bupropion
6) Liraglutide
Please Enter Your Response On Your Keypad
Investigations  Stratification
Front Line Clinical Applications
A Comparative Look at The Therapeutic Toolkit:
Putting Trial-Based Evidence into
Practice for Obesity Management
Safety and Efficacy of Agents Affecting CNS Signaling
Systems and Centrally-Mediated Appetite Regulation
Ken Fujioka, MD – Program Chair
Director, Nutrition and Metabolic Research Center | Director, Center
for Weight Management | Scripps Clinic in San Diego, CA
Obesity Pharmacotherapy
Obesity Pharmacotherapy
An adjunct to lifestyle modification
– not a substitute
Can increase chances of meaningful weight loss
2013 AHA/ACC/TOS Obesity Guideline:
Identify Patients Who Need to Lose Weight
 Recommendations serve as guide for PCPs in making
evaluations and treatment decisions for overweight and
obese patients
 Measure height and weight and calculate BMI at annual
visits or more frequently
 Advise overweight/obese adults that the greater the BMI, the
greater the risk of CVD, type 2 diabetes, and all-cause mortality
 Measure waist circumference at annual visits or more
frequently in overweight/obese adults
 Advise patients that the greater the waist circumference, the
greater the risk of CVD, type 2 diabetes, and all-cause mortality
BMI = body mass index; CVD = cardiovascular disease.
Jensen MD, et al. J Am Coll Cardiol. 2013 Nov 7. pii:S0735-1097(13) 060300-0. doi:10.1016/jacc.2013.11.004.
[Epub ahead of print].
141
Screening for Overweight/Obesity
in Caucasians
Disease Riska
BMI Classifications
Relative to Normal Weight and Waist
Circumferenceb
BMI
(kg/m2)
Obesity
Class
Men ≤40 in
Women ≤35 in
Men >40 in
Women >35 in
<18.5
-
-
-
Normal
18.5-24.9
-
-
-
Overweight
25.0-29.9
-
Increased
High
Obesity
30.0-34.9
I
High
Very High
Obesity
35.0-39.9
II
Very High
Very High
40.0+
III
Extremely High
Extremely High
Underweight
Extreme obesity
aDisease
bIncreased
risk for T2DM, hypertension, and CVD.
waist circumference also can be a marker for increased risk, even in
persons of normal weight.
BMI = body mass index.
National Heart, Lung, and Blood Institute.
142
http://www.nhlbi.nih.gov/guidelines/obesity/e_txtbk/txgd/4142.htm.
Accessed March 24, 2014.
Screening for Overweight/Obesity:
Asians and Hispanics
BMI and Waist Circumference
Classifications: Asians
BMI
(kg/m2)
Overweight
≥23-24 kg/m2
Obesity
≥25 kg/m2
BMI and Waist Circumference
Classifications: Hispanics
BMI
(kg/m2)
Overweight
?
Obesity
?
Waist Circumference
Waist Circumference
Women
>31.5 in
Women
>35 in
Men
>35 in
Men
>37 in
•
Asians have a smaller body build, but tend to accumulate more body fat and develop
CV risk factors at a lower body weight or smaller waist circumference than Caucasians
• The evidence is not as clear for Hispanics as Asians in regard to waist circumference
cutoffs and abdominal obesity
CV=cardiovascular; BMI = body mass index.
Chan J. Diabetes Voice. 2006;51:18-20; Aschner P, et al. Diabetes Res Clin Pract.2011;93:243-247.
AACE Complication-centric Model for
Care of the Overweight/Obese Patient
Reprinted from American Association of Clinical Endocrinologists. AACE/ACE Diabetes Algorithm for
Glycemic Control. Available at
https://www.aace.com/sites/default/files/GlycemicControlAlgorithmPPT.pdf. Accessed (22-Mar-16),
with permission from the American Association of Clinical Endocrinologists.
AACE medical complication Centric Algorithm
►
Step 1
●
●
►
Patient does not have a co-morbid obesity problem
Patient does have a co-morbid obesity problem
Step 2
●
●
●
Pt with no co-morbid problem BMI 25 or higher start
diet and lifestyle modification
Pt with co-morbid problem and BMI 27 or higher start
diet, lifestyle modification and weight loss medications
Pt with co-morbid problem and BMI 35 or higher
consider bariatric surgery
NHLBI Obesity Treatment Guidelines
A Guide to Selecting Treatment
BMI Category (kg/m2)
Treatment
25.0–26.9
27.0–29.9
30.0–34.9
35.0–39.9
≥40
Diet, physical
activity, and
behavior
Appropriate
NHLBI
Guidelines
+
+
+
+
Pharmacotherapy
No
With
comorbidities
+
+
+
Surgery*,†
No
No
No
LAGB only
With
comorbidities
+
†FDA-approved
*Bariatric surgeries require lifestyle medical follow-up.
gastric band surgery for patients with BMI ≥30 kg/m2 and one weight-related medical condition (February
2011).
LAGB = laparoscopic adjustable gastric banding; NHLBI = National Heart, Lung, and Blood Institute.
NHLBI. http://www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.htm. Accessed August 6, 2014.
1. Evaluation: BMI ≥25 kg/m2
2. Treat complications up front
“regardless of weight-loss efforts”
3. Assess lifestyle choices and
readiness to change, and set weightloss goals with patient
4. Comprehensive lifestyle intervention
with goal of 5%–10% weight loss
5. If weight loss is not ≥5%, add
medications
6. Consider bariatric surgery
7. Long-term follow-up
The 2013
TOS/AHA/ACC
Guidelines
Include a
Treatment
Algorithm
The Chronic Care
Model
of Weight
Management by
PCPs
Jensen MD, et al. Circulation. 2014;129(25
Suppl 2):S102-S138.
Anti-obesity Drugs Presently on the Market
and Pending Approval
FDA-Approved Drug
Benzphetamine
(Didrex)
Phendimetrazine
(Bontril)
Phentermine
(Adipex, Suprenza)
Diethylpropion
(Tenuate)
Orlistat
(Xenical) (Alli –OTC)
Company
Mechanism of Action
Comments
Pharmacia
Norepinephrine/dopamine
releasing stimulator
Schedule III drug, approved 1960
for short-term use
Valeant
Norepinephrine/dopamine
releasing stimulator
Schedule III drug, approved 1961
for short-term use
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
Phentermine/Topiramate
(Qysmia)
(formerly Qnexa)
Vivus
Noradrenaline releasing +
modulator of ɣ aminobutyric
acid (GABA)/ carbonic
anhydrase inhibition
Lorcaserin
(Belviq)
Arena
Pharma/Eisai
Selective 5-HT2Creceptor
agonist
Approved July 2012: for long term
use
Approved June 2012: for long term
use
Recently Approved End of 2014
Bupropion/Naltrexone
(Contrave)
Liraglutide
Orexigen
Inhibitor of dopamine and
noradrenaline reuptake +
µ opiate antagonist
Non Scheduled: for long term use
Novo Nordisk
GLP-1 agonist
Non Scheduled: for long term use
Modified from Zhi-yun Zhang Z-y and Wang M-w. Acta Pharmacologica Sinica 2012;33:145–147.
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.
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
100
150
200
250
300
350
400 mg
Phentermine
0
3.75
Low
5
7.5
Mid
10
15
Full
20
25
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
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.
30mg
(free base)
EQUIP
Phentermine/
Topiramate
Trials
CONQUER
SEQUEL
•Double-blind,
•Extension
placebo-controlled, three-arm, prospective study
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
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.
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
Heart rate (bpm)

74.7
65.4
Gadde KM, et al. Lancet. 2011;377(9774):1341-1352.
Metabolic Effects of Phentermine/Topiramate ER
in Non-Diabetic Patients: SEQUEL Study
Glucose
*
Insulin
*
*
*
*
Placebo
Phen/TPM ER 7.5/46 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.
*
Phen/TPM ER 15/92 mg
Phentermine/Topiramate ER: EQUIP and CONQUER
Most Commonly Reported Treatment Emergent Adverse Events
Adverse Event (%)
(N=3749)
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
Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012.
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
►
Phase 3 studies did allow patients on SSRIs with
stable depression
*Columbia Suicide Severity Rating Scale
** Patient Health Questionnaire 9-item depression scale
Phentermine and topiramate extended-release [package insert]. Mountain View, CA : Vivus; 2012.
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 child-bearing
potential recommend initial pregnancy test and monthly while
on medication
• 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.
Lorcaserin
Lorcaserin
Mechanism of Action
Indications and Dose
• Selective 5-HT2C
• Approved by FDA June
Receptor agonist
• Stimulates α-MSH
production from POMC
neurons resulting in
activation of MC4R
• Increases satiety
2012
• Indication: Weight loss
in patients with BMI
≥30 kg/m2 or BMI ≥27
kg/m2 with weightrelated co-morbid
condition(s)
• 10 mg po bid
• Schedule IV
• Discontinue if 5%
weight loss is not
achieved in 12 wks
Lorcaserin hydrochloride [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012.
Contraindications and
Warnings
Contraindications
• Pregnancy
Warnings
• Co-administration with
other serotonergic or
anti-dopaminergic agents
• Cognitive impairment
• Psychiatric disorders
(euphoria, suicidal
thoughts, depression)
• Priapism
• Risk of hypoglycemia with
diabetes meds
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 α-melanocyte-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.
Lorcaserin Phase 3 Trials
• n=3,182
• 2 years tx
• Dosage 10 mg QD1
•
•
•
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=4,008
1 year tx
Dosage 10 mg QD2
• n=604 obese/ overweight
with type 2 DM
• 1 year+ tx
• Dosage 10 mg BID
or 10 mg QD3
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%)
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.
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.
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.
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
Cardio Vascular outcome study was started due to concerns
about blood pressure and pulse
►
The Light Study (CVD trial) is under way; estimated
completion: July 2017
►
Interm-analysis showed no increase in Cardiovascular events
so the medication was approved
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
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.
Improvement in Risk Factors with Use of
Naltrexone SR / Bupropion SR
Measure
Week 28
Placebo N = 456
NB32 N = 825
P-value
Placebo N = 456
Week 56
NB32 N = 702
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
−0.5% (−6.5%, +5.9%)
−14.1% (−17.9%, −10.2%)
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%)
118.2 ± 10.5
117.9 ± 10.0
−0.5 ± 0.4
+0.6 ± 0.3
76.8 ± 7.0
76.7 ± 7.0
+0.3 ± 0.3
+0.4 ± 0.2
<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)
<0.001
<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
Baseline
76.8 ± 7.0
76.8 ± 7.0
Change
170
−0.7 ± 0.3
+0.2 ± 0.2
0.556
0.039
Diastolic blood pressure, mm Hg
0.017
Apovian CM, Aronne L, et al. Obesity (Silver Spring). 2013 May;21(5):935-43.
0.847
Side Effects
Naltrezone/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.
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 GLP1 receptors expressed on vagal afferents and brain
►
Favorably Affects visceral fat adiposity, appetite, food
preference, and cardiovascular biomarkers in patients
with type 2 diabetes
►
Suppresses appetite, and delays gastric emptying
►
3.0 mg/day approved for obesity treatment by FDA
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
Weight Loss Maintenance with Liraglutide
*Run-in length variable: individuals randomised to treatment arms once target ≥5% weight loss achieved
**0·6 mg weekly increments of liraglutide with escalation to 3·0 mg/day
Wadden, et al. 2011
BMI: body mass index, FPG: fasting plasma glucose
Weight Loss Maintenance with Liraglutide
Mean changes in body weight from week -14 (screening) to week 68
(follow-up).
S=screening. Observed mean data ± SEM for the full analysis set (n=413) are shown.
*The numbers shown are the numbers of individuals who were later randomised and comprised the full analysis set. 675 individuals were actually
screened. The numbers shown at weeks -8 and -2 are the numbers of individuals who remained to be randomised.
Wadden, et al. 2011
Side Effects
►
Liraglutide
Placebo
►
Nausea
39.3%
13.8%
►
Diarrhea
20.9%
9.9%
►
Constipation
19.4%
8.5%
►
Vomiting
15.7%
3.9%
►
Dyspepsia
9.6%
2.7%
►
Liraglutide Package insert 2015
Prevalence of Prediabetes and Metabolic Syndrome at
Randomization and After 1 and 2 Years of Treatment
Placebo
Prediabetes*
Proportion of individuals (%)
60
Orlistat
*P ≤.001 vs placebo
**P=0.005
#P=0.01
50
†P ≤.002 vs. orlistat
Liraglutide 1.8 mg
Liraglutide 2.4 mg
Liraglutide 3.0 mg
Liraglutide 2.4/3.0 mg
pooled group
P<.001
40
33
30
37
36 36
36
29
31
20
32
32
28
* *
†
†
*
† 11 10
7
10
Liraglutide 1.2 mg
16
0
Randomization
Year 1
Year 2
*As defined by the American Heart Association.
Astrup A, et al. Int J Obes (Lond). 2012;36:843-854; Grundy S, et al. Circulation. 2004;109:4330-438.
Obesity Drugs in the Pipeline
Beloranib
Beloranib: Phase 1 Trial Results – 4 weeks
Fumagillin-class methionine
aminopetidase-2 (MetAP2) inhibitor
Dosage
Weight Loss
(kg)
Placebo
0.1 mg/m2 (n=7)
0.3 mg/m2 (n=6)
0.9 mg/m2 (n=8)
-0.6 kg
(-4.5, -0.1)
►
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
-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]
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
No evidence of major tolerability or safety issues
(Phase 1 trials)
ADA Poster Session 19-B Abstract #188-LB June 22, 2013
•
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
Summary
►
Multiple choices of anti-obesity medications
►
Two new medications approved in 2012
►
Two more approvals in 2014
►
Medications can enhance weight loss for select
candidates and improve cardiometabolic outcomes
►
Medications are always only adjunct to diet and
exercise
►
Identifying non-responders to weight loss
medications will improve weight loss
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
Obesity Management
Case Study 4
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 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
Obesity Management
Case Study 5
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” she is staying at
home and not going out, poor self image
►
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
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 2
Which medication changes would you consider ?
1) Wean off paroxetine
2) Start Orlistat
3) Start Lorcaserin
4) Start Phentermine/topiramate ER
5) Start Phentermine
6) Start NaltrexoneER/BupropionER
7) Start Liraglutide
Please Enter Your Response On Your Keypad
Obesity Management
Case Study 6
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 mgs sub-q
●
Hypertension
• Losartan 100 mg q d, diltiazem 360, HCTZ 25 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 has 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 “it’s 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 to 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, and Lorcaserin
were discussed and asked her to review the
companys websites [Naltrexone/Bupropion
and 3.0 mgs Liraglutide were 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)