Charles SAAB MD / CEHP / MAACE . Consultant Endocrinologist. Dir.Clin.Res.Prog. . Dept of . Endoc&Metab. . Diseases SCUH – Beirut –Lebanon. President AACE Lebanon Chapter. MGSD Executive Board Member. ID: 672562
DownloadNote - The PPT/PDF document "Eating Behavior Defect: Consequences and..." is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Eating Behavior Defect: Consequences and New treatment Modalities
Charles SAAB MD / CEHP / MAACE Consultant EndocrinologistDir.Clin.Res.Prog. Dept of Endoc&Metab. Diseases SCUH – Beirut –LebanonPresident AACE Lebanon ChapterMGSD Executive Board MemberPast-President Lebanese Society Endoc.Diab&LipidsANNUAL LSEDL MEETING BEIRUT JUNE 30, 2017
1
Slide2OUTLINEOBESITY “A CHRONIC DISEASE”: THE EVIDENCE
THE “NORMAL” EATING BEHAVIORDEFECTS LEADING TO OBESITYNEW TREATMENT MODALITIES2
Slide33
40%201533%2008
# 50%
2025
CDC/NCHS
Data No. 219
November 2015
USA
Slide4Obesity is recognised as a disease and global health issue
“…obesity is a primary disease, and the full force of our medical knowledge should be brought to bear on the prevention and treatment of obesity as a primary disease entity”1
“Recognizing obesity as a disease will help change the way the medical community tackles this complex issue that affects approximately one in three
Americans”
2
“Obesity
is a
chronic disease
, prevalent in
both
developed and developing countries,
and
affecting children as well as
adults”
3
“FDA
agrees with these comments that
obesity is a
disease.” “Being overweight
,
ie
being more than one's ideal weight but less
than obese
, however, is not a
disease”
3
AACE, American Association of Clinical Endocrinologists; AMA, American Medical Association; FDA, Food and Drug Administration;
WHO, World Health Organization
References: 1
. Mechanick JI et al. Endocr Pract 2012; 18:642–8; 2. AMA. 2013. Available at: www.ama-assn.org/ama/pub/news/news/2013/2013-06-18-new-ama-policies-annual-meeting.page; 3. Allison DB et al. Obesity (Silver Spring) 2008; 16:1161–77.
4
Slide5Obesity Is a Major contributor to disease and is Associated With Comorbid Diseases
5aBased on a review of >1000 epidemiologic studies to assess the effects of weight control on cancer risk, performed by a working group of the International Agency for Research on Cancer (IARC).bBased on data from the 2001 Behavioral Risk Factor Surveillance Survey (BRFSS), including US residents aged 18 years and older.cBased on a meta-analysis summarizing available prospective cohort studies (as of March 2008).BMI=body mass index; CHD=coronary heart disease.1. Lauby-Secretan B et al. N Engl J Med. 2016;375:794-798. 2. Mokdad AH et al.
JAMA
. 2003;289:76-79. 3.
Luppino
FS et al.
Arch Gen Psychiatry
. 2010:67:220-229.
4. Mathew B et al.
J Am Board Fam Med
. 2008;21:562-568.
1.1–7.1x
increased risk for certain cancers
1a
including corpus uteri, esophageal, stomach, liver, kidney, pancreatic, meningioma,
multiple myeloma, colorectal, gallbladder, ovarian, breast, and thyroid
3–7x
higher prevalence of diabetes
2b
compared with normal-weight adults
55%
increased risk for depression
3c
among individuals with BMI ≥30 kg/m
2
~2x
increased risk for CHD and stroke4 compared with normal-weight adults
Slide6Obesity Is a Chronic Condition With Serious Implications for Life Expectancy1
6aBased on a meta-analysis of 57 international prospective studies predominantly based in Europe, the United States, and Australia, including BMI information for 894,576 adults.BMI=body mass index.1. Whitlock G et al. Lancet. 2009;373:1083-1096. 2. Garvey WT et al. Endocr Pract. 2016;22(Suppl 3):1-203.
BMI
2
:
Healthy weight
Overweight
Obesity
18.5
30+
25
BMI 30–35 kg/m
2
Life expectancy reduced
2–4 years
BMI 40–50 kg/m
2
Life expectancy reduced
8–10 years
Each 5 kg/m
2
higher BMI
~40% higher mortality rate
for ischemic heart disease, stroke, and other vascular
diseases
a
Slide7Modest Weight Loss Helps to Confer Health Benefits for Patients With Obesity
Weight loss has been associated with:7HbA1c=hemoglobin A1c; HDL=high-density lipoprotein.1. Wing RR et al. Diabetes Care. 2011;34:1481-1486. 2. Courcoulas AP et al. JAMA. 2013;310:2416-2425. 3. Hassan MK et al. Int J Obes Relat Metab Disord. 2003;27:1227-1232.
4.
Sarwer
DB et al.
Eur
Eat
Disord
Rev
. 2015;23:504-508. 5. Hamman RF et al.
Diabetes Care
. 2006;29:2102-2107. 6. Held M et al.
PLoS
One
. 2014;9:e107480.
Significant improvements in
cardiometabolic
risk factors
1
HbA
1c
,
Fasting glucose,
Blood pressure,
Triglycerides, HDL cholesterol
Improvement or remission in diabetes, dyslipidemia, and hypertension2
Improvements in obesity-associated comorbidities and quality of life domains
3,4Reduced risk of diabetes5
Significant improvements in pulmonary function
6
Slide8Disrupture
of Energy-balance equation
Intake
Expenditure
Hunger
Satiety
Nutrient
absorption
Metabolic
rate
Thermogenesis
Exercise
NEAT
NEAT, non-exercise activity thermogenesis
8
WHAT LEADS TO OBESITY?
Slide9Normal Eating Behavior & Defects…
Food
Amounts
Time
Hunger(start)
Appetite
Palatability
Appetite
Satiation
Satiation
Alliesthesia
Priv
Coll
CS
2002
Satiety
THIS DEFECTS MAY LEAD
TO
FOOD “ADDICTION”
& OBESITY
9
Hunger
Hedonic
Slide1010
GENETICSEPIGENETICS
Slide1111
E.Finger : EAS 2011 GOTHENBURG-SWEEDEN
Slide12
AND… EXERCISE A LOOOOOOOOOT
Slide13Slide14Complexity of Eating Behavior
14
Slide1515
Complex Obesity Causes Require New Approach…
Endocrine Society outlines mechanisms underlying obesity epidemic
June 29, 2017
A growing body of research indicates that obesity is a
disorder of the energy homeostasis system
, according to a new Endocrine Society scientific statement.
The statement appeared online in the Endocrine Society's journal,
Endocrine Reviews 2017
Dysregulation
of Energy homeostasis (balance)
as Major Obesity
mecanism
Slide16Multiple (Neuro-Endocrine) signals influence EB
1–3CCK, cholecystokinin; GLP-1, glucagon-like peptide-1; OXM, oxyntomodulin; PP, pancreatic polypeptide; PYY, peptide YYReferences: 1. Berthoud HR, Levin BE. In: Handbook of Obesity. Epidemiology, Etiology and Physiopathology, 2014; 2. Woods SC, Seeley RJ. Int
J Obes Relat
Metab
Disord
2002; 26:S8–10
;
3.
Badman
MK, Flier JS.
Science
2005; 307:1909–14.
16
Adipose tissue
Leptin, adiponectin,
resistin
Gut
GLP-1, ghrelin,
OXM, PYY, CCK, lipids
Pancreas
Amylin, insulin, PP
Circulation
Hypothalamus, brainstem,
c
orticolimbic system
Meal
timing/size
Energy
expenditure
Nodose
ganglion
(
Convay
taste)
Vagus
nerve
Spinal
cord
Dorsal
root
ganglion
(sensations
Chemo
mechanics)
Hedonic inputs
(reward)
Slide17Reward-driven (hedonic) feeding has a different basis than physiological hunger1
Reference: 1.
Appelhans
BM.
Obesity (Silver Spring
)
2009; 17:640–7.
Prefrontal cortex,
mesolimbic dopamine system
Delay discounting
Feeding behaviour
Selective attention
17
Social
Food costs
Food availability
Palatable food
( override Satiety
)
Adipose tissue
Pancreas
Gut
Circulation
Leptin, adiponectin,
resistin
GLP-1, ghrelin,
OXM, PYY, CCK, lipids
Amylin, insulin, PP
Neural system
Hedonic inputs
(not
calory
related)
CCK
,
cholecystokinin; GLP-1,
glucagon-like
peptide-1; OXM, oxyntomodulin; PP, pancreatic polypeptide; PYY, peptide YY
“Evolved to protect
against
starvetion
and
promote fat storage”
Slide18Peripheral signals modulate appetite and energy expenditure through hypothalamic neurons
1
Effectors
Hypothalamus
Feeding
Gastric emptying
Metabolic rate
Hindbrain
Non conscious
Function
Vagal afferents
Nucleus tractus solitarius
Hunger
Satiety
Second-order
neurons
MC4R
Y1/Y5R
AgRP
α
-MSH
Arcuate
nucleus
Ghrelin
Hunger signals
NPY/
AgRP
POMC/CART
Leptin Insulin
Adiposity signals
PYY GLP-1
Satiety peptides
Appetite
Appetite
AgRP, agouti-related protein;
α-
MSH,
α-
melanocyte‒stimulating hormone; CART, cocaine and amphetamine regulated transcript;
GLP-1R
, glucagon-like peptide-1 receptor; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; PYY, polypeptide
YY
Reference: 1.
Badman
MK,
Flier JS.
Science
2005; 307:1909‒14.
18
Slide19ANY LONG TERM DISRUPTION OF THIS WELL REGULATED CLOCK, WILL LEAD TO AN EATING BEHAVIOR WITH A POSITIVE FEED BACK … LEADING TO O-W & OBESITY
19
Slide20References: 1.
Woods SC, Seeley RJ. Int J Obes Relat Metab Disord 2002; 26:S8–10; 2. Ludwig DS, Friedman MI. JAMA 2014; 311:2167–8; 3. Speliotes
EK
et al.
Nat
Genet
2010; 42:937–48;
4
.
Garvey
WT
et al.
Endocr
Pract
2014; 20:977–89;
5
.
Bray
GA, Ryan
DH. Ann NY Acad Sci 2014; 1311:1–13; 6. Guyenet SJ, Schwartz MW. J Clin
Endocrinol Metab 2012; 97:745–55.
Obesity is a complex and multifactorial disease
1–6
Adipose tissue
Gut
Pancreas
Genetics
Medications
Experienced palatability or pleasure
Hedonic input
20
Energy expenditure
Energy intake
Socioeconomic
Environment
Slide21High obesity
rates NOT explained by genes only 21References: 1. Davidson TL et al. J Exp Psychol Anim Learn Cogn 2014; 40:261–79; 2. Making Health Easier. Available at:
http://makinghealtheasier.org/newabnormal
;
3.
Egger G, Dixon J.
Biomed Res Int
2014
; 2014:731685
;
4
.
Milagro
FI
et al.
Mol
Aspects
Med
2013
; 34:782–812.
Dramatic changes in the
“food environment”1We are eating larger portions and thus greater meal sizes2
Other contributing factors
3
DNA
methylation
// Epigenetic modifications?
4
Slide22QUICK LSM
1950(RURAL) 2012(URBAN)68% OW/OBESE
Slide23KUWAIT 1955
KUWAIT 2010 > 75% OW
Slide241955
201525-30% OBESE
Slide25Adding to Complexity of the Disease: Hormonal status after weight loss
25From Sumithran P, et al,1 ©2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.CCK=cholecystokinin; ITT=intent to treat; YY=tyrosine tyrosine.1. Sumithran P et al. N Engl J Med. 2011;365:1597-1604.Amylin, pg/mL
Postprandial Time, min
0
180
240
30
60
120
200
100
0
Week 62
Baseline
Appetite Suppressing Hormone Was Lower
Appetite Stimulating Hormone Was Higher
Ghrelin, pg/mL
0
180
240
30
60
120
200
100
0
Postprandial Time, min
Week 62
Baseline
Appetite Suppressing Hormone Was Lower
CCK, fmol/mL
Postprandial Time, min
0
180
240
30
60
120
4
2
0
1
3
Week 62
Baseline
Appetite Suppressing Hormone Was Lower
Peptide YY, pg/mL
60
20
0
0
180
240
30
60
120
Postprandial Time, min
Week 62
Baseline
Compensatory mechanisms encourage weight regain after weight
loss
1
Slide26Prevention of obesity is the key,
But in Overt obesity could we intervene??? 26Effective Treatment Options
Slide27AHA/ACC/TOS Guideline-Recommended Obesity Management Options1,a
27Patients with BMI ≥40 kg/m2Patients with BMI ≥35 kg/m2 and obesity-related comorbiditiesMotivated to lose weight
Have not responded to previous behavioral treatment (with or without pharmacotherapy)
Pharmacotherapy
Surgery
Patients with BMI ≥30 kg/m
2
Patients with BMI ≥27 kg/m
2
and
≥1 obesity-related comorbidity
(
eg
, hyperlipidemia, hypertension, T2DM)
Motivated to lose weight
Lifestyle modifications, the backbone of treatment,
include dietary modifications, exercise, and behavioral changes
Recommended as adjunct to lifestyle modifications:
a
According
to recommendations from the AHA/ACC/TOS 2013 obesity treatment guidelines, created in collaboration with the NIH-NHLBI.
ACC=American College of Cardiology; AHA=American Heart Association; BMI=body mass index; NHLBI=National Heart, Lung, and Blood Institute; NIH=National Institutes of Health;
T2DM=type 2 diabetes mellitus; TOS=The Obesity Society.
1. Jensen MD et al.
Circulation
. 2014;63:2985-3023.
Slide28MARKETED DRUGS IN 2017(ONE DRUG & COMBI)
Slide29AMPHETAMIN DERIVED/SHORT TERMUSA
Drugs for short-term treatment (8-12 weeks) Diethylpropion, (TENUATE®)Phendimetrazine, (OBEZINE®,ADIPOST®…)Benzphetamine, (DIDREX®) Phentermine, (ADIPEX®…)29
Slide30Orlistat
-induced Weight Loss*
Change in
body weight
(%)
0
–2
–4
–6
–8
–10
–12
–4
0
10
20
30
40
52
Week
Placebo (n=340)
Xenical
®
120 mg (n=343)
*
p<0.001
–6.1%
–10.2%
ITT population: BM14119C
(Sjöström L, et al. Lancet 1998, 352; 167
172)
30
Slide31LORCASERIN Lorcaserin
Selectively activate 5-HT 2C receptors on anorexigenic pro-opiomelanocortin neurons in the hypothalamus. Approved by the FDA in June 2012 as an adjunct to a reduced-calorie diet and exercise for long-term weight management in individuals with an initial BMI of> 30 kg/m2 31
Slide3232
Slide33LIRAGLUTIDE 3 MG
33LIRAGLUTIDE
Slide34COMBINATION DRUG APPROACH
34
Slide35Phentermine / Topiramate XR
Phentermine and topiramate XR Approved by the FDA in July 2012 as an adjunct to a reduced-calorie diet and exercise for long-term weight management in individuals with an initial BMI of 30 kg/m2.CNS adverse effects such as drowsiness, paresthesias, memory loss, and confusion are causes of concern. 35
Slide36PT PROFILE
Jennifer Morrow (MEDSCAPE SEPT 2012) 36
Slide37Naltrexone/Bupropion (NB) Overview & MOA
37
Slide38NB Is a Combination of Two Compounds:Naltrexone and Bupropion1
38Naltrexone HCl1,2An opioid receptor antagonistIndications: treatment of alcohol dependence and prevention of relapse to
opioid dependence
FDA approved since
1984
Bupropion HCl
1,3,4
A dopamine and norepinephrine reuptake inhibitor
Indications:
major depressive disorder
and
as an aid to
smoking cessation
FDA approved since
1985
FDA=Food and Drug Administration.
1.
Contrave
[prescribing information]. La Jolla, CA:
Orexigen
Therapeutics, Inc.; 2016. 2.
Vivitrol® [package insert]. Waltham, MA: Alkermes; 2015. 3. Wellbutrin SR [package insert].
Research Triangle Park, NC: GlaxoSmithKline; 2014. 4. Zyban [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.
NB
is available in a unique formulation of extended-release tablets that contain
8 mg naltrexone
HCl
and 90 mg bupropion HCl1:
Slide39Naltrexone and Bupropion Act Synergistically to Activate the POMC Neurons in the Hypothalamic Hunger System, Resulting in Appetite Suppression1
39Figure adapted from Billes et al,1 © 2014, with permission from Elsevier.MSH=melanocyte-stimulating hormone; POMC=pro-opiomelanocortin. 1. Billes SK et al. Pharmacol Res. 2014;84:1-11.
Increased POMC activity
Reduced Hunger
Reduced Weight
Hypothalamus
Bupropion
Directly increases POMC activity
POMC
neuron
Naltrexone
Indirectly increases POMC activity by blocking
the
negative feedback loop
β-endorphin
α
-
MSH
Slide40↓ Appetite↑ Energy Expenditure
Naltrexone/Bupropion: Influence on Energy Balance and Reward140Figure adapted from Billes et al,1 © 2014, with permission from Elsevier.MC4-R=melanocortin-4 receptor; MSH=melanocyte-stimulating hormone; POMC=pro-opiomelanocortin. 1. Billes SK et al. Pharmacol Res. 2014;84:1-11.
Hypothalamus
MC4-R
α
-
MSH
Bupropion
POMC stimulus
POMC
neuron
Naltrexone
µ-opioid receptor
POMC negative feedback loop
(
β-
endorphin
)
Weight loss
MC4-R gene mutations associated with
INHERITED HUMAN OBESITY/ FEEDING/ED/
SEXUAL BEHAVIOR
Mesolimbic
Reward System
Slide41NB Phase 3 Clinical Development Program41
Slide42Efficacy and Safety of NB Was Assessed in a Comprehensive Phase 3 Clinical Development Program1
42aBMOD consisted of group sessions led by dietitians, psychologists, or exercise specialists to educate subjects on weight control techniques. Subjects were also asked to follow individualized hypocaloric diets and were encouraged to increase moderately vigorous physical activity from 180 min/week to 360 min/week.BMI=body mass index; BMOD=behavior modification; NB16=naltrexone 16 mg SR/bupropion 360 mg SR; NB32=naltrexone 32 mg SR/bupropion 360 mg SR; T2DM=type 2 diabetes mellitus.1. Contrave [prescribing information]. La Jolla, CA: Orexigen Therapeutics, Inc.; 2016. 2. Greenway FL et al. Lancet. 2010;376:595-605. 3. Apovian CM et al. Obesity. 2013;21:935-943. 4. Wadden TA et al.
Obesity
. 2011;19:110-120. 5. Hollander P et al.
Diabetes Care
. 2013;36:4022-4029.
COR-BMOD
4
N=793
COR-I
2
N=1742
COR-DM
5
N=505
COR-II
3
N=1496
Behavioral modification
Type 2 diabetes
The clinical development program consisted of four 56-week, placebo-controlled studies
(N=4536 subjects)
Study Design
56 weeks, placebo-controlled, including 3-week dose escalation
(COR-II: primary endpoint 28 weeks)
Population
BMI 30
45 kg/m
2
BMI 27
45 kg/m
2
(with comorbidities)
T2DM, BMI 27
45 kg/m
2
Diet and
Exercise
Diet and exercise counseling
Intensive
BMOD
a
Diet and exercise counseling
Dose and Randomization
NB16 and NB32
1:1:1
NB32
2:1
NB32
3:1
NB32
2:1
Slide43Phase 3 Clinical Development Program: Baseline Characteristics1
43
Mean=
46 years
Age
Men:
17%
Women:
83%
Sex
Mean=
36 kg/m
2
BMI
Mean=
110 cm
Waist Circumference
White:
77%
Black:
18%
Other:
5%
Race
Hypertension:
24%
Dyslipidemia:
54%
Type 2 diabetes:
10%
Comorbidities
BMI=body mass index.
1.
Contrave
[prescribing information]. La Jolla, CA:
Orexigen
Therapeutics, Inc.; 2016.
Subject Characteristics Across All 4 Phase 3 Trials (N=4536)
Slide44NB Was Significantly More Efficacious Than Placebo in Phase 3 Trials
1-444 NB
Placebo
LS Mean % Change in
Body Weight From Baseline
*
*
*
*
*
*
COR-BMOD
1,3
COR-I
1,2
COR-DM
1,4
Average weight loss of 25 pounds in patients completing 56 weeks
of therapy with NB
(COR-BMOD)
1,3
n=536
n=538
n=196
n=565
n=166
n=321
n=290
n=296
n=106
n=301
n=100
n=175
*
P
<0.001 vs placebo.
BMOD=behavior modification; DM=diabetes mellitus; ITT=intent-to-treat; LS=least squares; T2DM=type 2 diabetes mellitus.
1.
Contrave
[prescribing information]. La Jolla, CA:
Orexigen
Therapeutics, Inc.; 2016. 2. Greenway FL et al.
Lancet
. 2010;376:595-605. 3.
Wadden
TA et al.
Obesity
. 2011;19:110-120.
4. Hollander P et al.
Diabetes Care
. 2013;36:4022-4029.
Treatment with NB resulted in significant weight loss at 56 weeks
Slide45The Percentage of Subjects With ≥5% or ≥10% Body Weight Loss
Was Greater With NB Compared With Placebo in Phase 3 Trials
1-3
45
% of Patients
(Co-Primary Endpoint)
NB
Placebo
≥
5% Weight Loss
≥
10% Weight Loss
62
23
24
53
11
34
30
55
8
26
a
Completer
population at 56-week endpoint.
BMOD=behavior modification; DM=diabetes mellitus.
1. Greenway FL et al.
Lancet
. 2010;376:595-605. 2.
Wadden
TA et al.
Obesity
. 2011;19:110-120. 3. Hollander P et al.
Diabetes Care
. 2013;36:4022-4029.
More patients taking NB achieved ≥5% or ≥10% weight loss from baseline at 56 weeks than placebo (completer analysis)
a
Slide46Mean Percent Change in Total Body Fat Mass With NB Plus Diet and Exercise at 52 Weeks1
46A subset of COR-I patients (n=124; LOCF) were assessed for body composition using DEXA
COR-I
sub-study
Mean Change From Baseline (%)
Placebo
+ diet and exercise
(n=45)
NB
+ diet and exercise
(n=79)
*LOCF; Treatment Difference, -7.4% (-7.3
lb
),
P
<0.01.
DEXA=dual energy X-ray absorptiometry; LOCF=last observation carried forward.
1.
Contrave
[prescribing information]. La Jolla, CA:
Orexigen
Therapeutics, Inc.; 2016.
Weight loss with NB plus diet and exercise was associated with a significant decrease in mean total body fat mass
Slide47NB Treatment Resulted in Greater Reductions in Waist Circumference Compared With Placebo1
47
LS Mean Change from Baseline (inches)
*
*
*
P
<0.001 vs placebo.
a
Full
analysis set, LOCF: based on 56-week endpoint.
BMOD=behavior modification; DM=diabetes mellitus; LOCF=last observation carried forward; LS=least squares.
1.
Contrave
[prescribing information]. La Jolla, CA:
Orexigen
Therapeutics, Inc.; 2016.
Reductions in waist circumference from baseline at 56 weeks was greater in patients taking NB compared with placebo
a
Inche
=2.5 cm
Slide48NB Has Demonstrated Improvements in Glycemic Control1,2
48-0.1%
-0.6%
*
*
*
*
44.1%
of patients
achieved
HbA1c
<7
%
(44.1
vs.
placebo 26.3
%;
P<0.001)
Baseline HbA
1c
=8.0%
Republished with permission of the American Diabetes Association, from Hollander P et al,
2
© 2013; permission conveyed through Copyright Clearance Center, Inc.
*
P
<0.001 vs placebo.
a
mITT-LOCF.DM=diabetes mellitus; HbA1c=hemoglobin A1c; LS=least squares; mITT-LOCF=modified intent-to-treat/last observation carried forward; T2DM=type 2 diabetes mellitus.
1. Contrave [prescribing information]. La Jolla, CA: Orexigen Therapeutics, Inc.; 2016. 2. Hollander P et al. Diabetes Care. 2013;36:4022-4029.
Patients with T2DM had significantly improved mean HbA1c levels with NB treatment compared with placebo over 56 weeks
a
COR
-DM
Slide49Mean Changes in Several Cardiometabolic Risk Factors With NB Plus Diet and Exercise
1-349aBased on LOCF (last observation carried forward) while on study drug.bChanges in triglycerides and HDL achieved statistical significance as reported in the primary manuscripts.2,3BMOD=behavioral modification; HDL=high-density lipoprotein; LDL=low-density lipoprotein; LS=least squares.1. Contrave [prescribing information]. La Jolla, CA: Orexigen Therapeutics, Inc.; 2016. 2. Greenway FL et al. Lancet. 2010;376:595-605. 3. Wadden TA et al. Obesity. 2011;19:110-120.
No significant differences were observed between groups in LDL cholesterol
2,3
COR-BMOD
COR
-I
COR-BMOD
COR-I
HDL Cholesterol
Triglycerides
Median Change
From Baseline (%)
LS Mean Change
From Baseline (%)
NB treatment resulted in greater improvements in triglycerides and HDL cholesterol compared with placebo
a,b
NB
Placebo
COR-BMOD
COR
-I
Slide50RESULTS ON FOOD CRAVING
50
Slide51Safety Evaluated in 5 Double-Blind Placebo-Controlled Trials in 4754 Patients Up to 56 Weeks1,a
51Adverse Reaction
NB
32 mg/360 mg
n=2545
Placebo
n=1515
Nausea
32.5%
6.7%
Constipation
19.2%
7.2%
Headache
17.6%
10.4%
Vomiting
10.7%
2.9%
Dizziness
9.9%
3.4%
Insomnia
9.2%
5.9%
Dry mouth
8.1%
2.3%
Diarrhea
7.1%
5.2%
a
2545 patients received naltrexone
HCl
/bupropion
HCl
32 mg/360 mg total daily dose; some patients were treated with other combination daily doses. 1515 patients were treated with placebo.
1.
Contrave
[prescribing information]. La Jolla, CA:
Orexigen
Therapeutics, Inc.; 2016.
Adverse reactions reported with ≥5% incidence with NB and more commonly than placebo:
Slide52LIGHT STUDY / (NB)CVOT 52
PRIMARY ENDPOINT: TIME TO FIRST MACE
Slide53Nalterxone/ Bupropion Precautions1
No suicide or suicide attempts were reported in studies up to 56 weeks duration with naltrexone/ bupropion and suicidal ideation was not more commonly reported in subjects treated with naltrexone/ bupropion compared to placeboHepatotoxicity: Cases of hepatitis and clinically significant liver dysfunction observed with naltrexone exposureAngle-closure glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with
antidepressants
Use of Antidiabetic Medications:
Weight loss may cause hypoglycemia. Monitor blood glucose
1.
Contrave
[prescribing information]. La Jolla, CA:
Orexigen
Therapeutics, Inc.; 2016.
53
Slide54SUMMARY/CONCLUSIONObesity is a chronic, relapsing disease that requires long-term treatment
There are hormonal, physiologic, genetic and epigenetic adaptations our body exhibits to MAINTAIN adiposity by hindering weight loss and promoting weight gainRealistic expectations of 5-10% weight loss is achievable and has shown to produce significant improvement of multiple co-morbid medical problems.Behavior modification remains the cornerstone of treatment , helped with safe and efficient pharmacotherapies acting on both mesolimbic reward and Hypothalamic hunger systems54
Slide55THANK YOU 55
Slide56Some Pathways through Which Excess Adiposity Leads to Common Chronic Diseases.
Heymsfield SB, Wadden TA. N
Engl
J Med 2017;376:254-266
Slide57METFORMIN IN IGT?
Meta-analysis1: metformin treatment in obese persons at risk for diabetes mellitus. 31 Trials RCT n= 4500Decrease weight, (-3Kg/Y)Improve lipid profilesImproves insulin sensitivity,and reduces new-onset diabetes by 40%.1.Salpeter SR,Am J Med Feb 2008; 121(2)
57
Slide58Components of NB Individually Interact With the
Mesolimbic
Reward System Resulting in Long-term Behavior Change
1
58
Nucleus
Accumbens
Ventral
Tegmental Area
Naltrexone HCl
1,4
Bupropion HCl
1,2,3
Indicated for the treatment of
major depressive disorder
and
as an aid to
smoking cessation
Indicated for the treatment of
alcohol dependence
and for prevention of relapse to
opioid dependence
Mesolimbic Reward System
Figure adapted from
Billes
et al,
1
© 2014, with permission from Elsevier.
1.
Billes
SK et al.
Pharmacol
Res
. 2014;84:1-11. 2. Wellbutrin SR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.
3.
Zyban
[package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 4.
Vivitrol
®
[package insert]. Waltham, MA:
Alkermes
; 2015.
Slide59Components of NB Also Individually Interact With the Hypothalamic Hunger System to Affect Appetite1
59Figure adapted from Billes et al,1 © 2014, with permission from Elsevier.POMC=pro-opiomelanocortin. 1. Billes SK, et al. Pharmacol Res. 2014;84:1-11.
Hypothalamus
Naltrexone
HCl
Bupropion
HCl
Indicated for the treatment of
major depressive disorder
and
as an aid to
smoking cessation
Indicated for the treatment of
alcohol dependence
and for prevention of relapse to
opioid dependence
Mesolimbic Reward System
Stimulates
POMC cells
, which suppresses appetite
Blocks
β-endorphin negative feedback loop
on POMC neurons, which further contributes to appetite suppression
Hypothalamic Hunger System
Slide60Combination Naltrexone + Bupropion Resulted in Greater Weight Loss vs the Individual Components1
60*Data are for Completer Population.IR=immediate release; SR=sustained release.1. Greenway FL et al. J Clin Endocrin Metab. 2009;94:4898-4906.
Naltrexone 32 mg IR + Bupropion 400 mg SR (n=45)
Bupropion 400 mg SR (n=44)
Naltrexone 48 mg IR (n=33)
Placebo (n=60)
Naltrexone + Bupropion
Bupropion
Naltrexone
Placebo
-4.8%
Change in body weight
Potential Synergistic Effect
Phase 2 Study Completers at 24 Weeks*
Slide61NB Dosing and Administration1
61NB dosing should be escalated over a 4-week period
Morning
Evening
Week 1
Week 2
Week 3
Week 4 and onwards
Administration
Tablets should be taken by mouth in the morning and evening and
should not be cut, chewed or crushed
In clinical trials, NB was administered with meals. However, NB
should not be taken with a high-fat meal
because of a resulting significant increase in bupropion and naltrexone systemic exposure
The need for treatment should be evaluated after 16 weeks and reevaluated annually.
1.
Contrave
[prescribing information]. La Jolla, CA:
Orexigen
Therapeutics, Inc.; 2016.
The maximum recommended daily dose of NB is 2 tablets twice daily for a total dose of
32 mg naltrexone
HCl
and 360 mg bupropion HCl
1
Slide62Studies in twins estimate the heritability of BMI as 40–80% in children and adults1,2Genome-wide association studies have identified a large number of genetic loci associated with obesity risk3
In one meta-analysis, the most common 97 loci only accounted for 2.7% of BMI variance, while genome-wide estimates accounted for ~20%4Therefore, a large proportion of heritability remains unexplained3It has been proposed that epigenetic modifications could account for some of this ‘missing’ heritability3Epigenetics may help to explain the heritability of obesity62
BMI, Body Mass Index
References
: 1.
Stunkard
AJ
et al.
N Engl J
Med
1990; 322:1483–7;
2.
Wardle J et al.
Am
J Clin
Nutr 2008; 87:398–404;
3
.
van Dijk
SJ et
al.
Clin
Epigenetics 2015; 7:66; 4. Locke AE et al. Nature 2015; 518:197–206.
Slide63Obesity Remains Undertreated Compared With Type 2 Diabetes1
Almost half of the adults in the United States meet recommendations for anti-obesity pharmacotherapy; however, only 2% of those adults receive proper pharmacotherapy treatment a63Figure adapted from Thomas et al,1 © 2016 The Obesity Society, with permission from John Wiley and Sons.aAnti-obesity pharmacotherapy is indicated as an adjunct to diet and physical activity in adults with a BMI ≥30 kg/m2 or ≥27 kg/m
2
with hypertension, type 2 diabetes, or dyslipidemia.
1. Thomas CE et al.
Obesity
. 2016;24:1955-1961.
US Adult Population (%)
2%
of adults with
obesity
received pharmacotherapy
86%
of adults with
T2DM
received pharmacotherapy
Slide64Nonclinical Studies Suggest NB Affects Both the Hypothalamic Hunger and Mesolimbic Reward Systems1
64POMC=pro-opiomelanocortin; VTA=ventral tegmental area.1. Contrave [prescribing information]. La Jolla, CA: Orexigen Therapeutics, Inc.; 2016.
The exact neurochemical effects of combined NB leading to weight loss are not fully understood
Combined, naltrexone and bupropion reduced food intake when injected directly into the
VTA
of the mesolimbic circuit in mice, an area associated with regulation of reward pathways
1
Mesolimbic Reward System
1
Combined, naltrexone and bupropion increased the firing rate of
POMC
neurons
in vitro
, which are associated with the regulation of appetite
1
Hypothalamic Hunger System
1
Slide65PRAMLINTIDEPramlintide (Symlin
):synthetic analogue of the pancreatic hormone amylin, used T1D/T2D does not have an FDA indication for obesity managementClearly associated with variable weight loss in people with type 1 or 2 diabetes.65
Slide66Weight Loss at 1 Year with High-Intensity Lifestyle Interventions or Pharmacotherapy
Combined with Low-to-Moderate-Intensity Lifestyle Counseling.
Heymsfield
SB,
Wadden
TA. N
Engl
J Med 2017;376:254-266
>15% W # 16%Pts
Slide67The Percentage of Subjects With ≥5% or ≥10% Body Weight Loss Was Greater With NB Compared With Placebo in Phase 3 Trials1
67*P<0.01 vs placebo; **P<0.001 vs placebo.BMOD=behavior modification; DM=diabetes mellitus; ITT=intent-to-treat; LOCF=last observation carried forward; LS=least squares.1. Contrave [prescribing information]. La Jolla, CA: Orexigen Therapeutics, Inc.; 2016.
More patients taking NB achieved ≥5% or ≥10% weight loss from baseline at 56 weeks than placebo (ITT-LOCF analysis)
% of Patients
(Co-Primary Endpoint)
≥
5% Weight Loss
≥
10% Weight Loss
**
42
17
18
**
36
7
**
21
21
**
35
5
*
15
43
**
57
NB
Placebo
Slide6868
Slide69Today's Top Docs
Related Slides
Credit Card Debt Good vs. Bad Debt
Missouri Division of Behavioral Health
Key Concepts in Nutrition
Interestingly Colored Beaches
Binge Eating Disorder:
Truth or Consequences Standard
Consequences
Consequences of uncontrolled e
BEHAVIOR-BASED SAFETY What inf
Consequences Unpacked Conseque
BEHAVIOR-BASED SAFETY
Consequences for Problem Behav
Consequences for Problem Behav