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Slide Source:www.obesityonline.org
The Efficacy of Pharmaceutical and The Efficacy of Pharmaceutical and Surgical Approaches to weight lossSurgical Approaches to weight loss
Valentine J. Burroughs, MD MBA
Chief Medical Officer
North General Hospital, New York, New York
University of Medicine and Dentistry of New Jersey
Newark, New Jersey
March 31, 2007
Slide Source:www.obesityonline.org
Principles of Pharmacotherapy Principles of Pharmacotherapy in the Management of Obesityin the Management of Obesity
Slide Source:www.obesityonline.org
Drugs Approved by FDA for Treating ObesityDrugs Approved by FDA for Treating Obesity
Generic NameTrade Names
DEA Schedule
Approved Use
Year Approved
Orlistat Xenical None Long-term 1999
Sibutramine Meridia IV Long-term 1997
Diethylpropion Tenulate IV Short-term 1973
PhentermineAdipex, lonamin
IV Short-term 1973
PhendimetrazineBontril, Prelu-2
III Short-term 1961
Benzphetamine Didrex III Short-term 1960
Slide Source:www.obesityonline.org
-32
-28
-24
-20
-16
-12
-8
-4
0
Effect of Continuous and Intermittent Effect of Continuous and Intermittent Phentermine Therapy on Body WeightPhentermine Therapy on Body Weight
0
Time (weeks)
8 24 28
Munro JF et al. Brit Med J 1:352, 1968
Wei
ght L
oss
(lbs)
364 12 16 20 32
Alternate Phentermine and Dummy
ContinuousPhentermine
Continuous Dummy
Slide Source:www.obesityonline.org
Drugs Approved by FDA for Treating ObesityDrugs Approved by FDA for Treating Obesity
Generic NameTrade Names
DEA Schedule
Approved Use
Year Approved
Orlistat Xenical None Long-term 1999
Sibutramine Meridia IV Long-term 1997
Diethylpropion Tenulate IV Short-term 1973
PhentermineAdipex, lonamin
IV Short-term 1973
PhendimetrazineBontril, Prelu-2
III Short-term 1961
Benzphetamine Didrex III Short-term 1960
Slide Source:www.obesityonline.org
Orlistat Prevents Fat Digestion and Absorption Orlistat Prevents Fat Digestion and Absorption by Binding to Gastrointestinal Lipasesby Binding to Gastrointestinal Lipases
TG=triglyceride; MG=monoglyceride; FA=fatty acid.
Mucosal CellMucosal CellIntestinal LumenIntestinal Lumen
OrlistatOrlistat TGTG
LIPASELIPASE
LIPASELIPASE
LIPASELIPASE
Bile AcidsBile AcidsMicelleMicelle
MGMGFAFA
Slide Source:www.obesityonline.org
0
10
20
30
40
50
60
Effect of Orlistat Dose on Fecal Fat Effect of Orlistat Dose on Fecal Fat ExcretionExcretion
Zhi et al. Clin Pharmacol Ther 1994;56:82.
Fe
cal F
at E
xcre
tion
(%
inta
ke)
Orlistat Daily Dose (mg)
0 200 400 600 800 1000 1200
Slide Source:www.obesityonline.org
-12
-9
-6
-3
0
Effect of Long-term Orlistat Therapy on Effect of Long-term Orlistat Therapy on Body WeightBody Weight
0Weeks
52
Torgenson et al. Diabetes Care 2004;27:155
Cha
nge
in W
eigh
t (kg
)
104 156 208
P<0.001 vs placebo
-4.1 kg
-6.9 kg
Placebo
Orlistat
Slide Source:www.obesityonline.org
Meta-analysis of RCTs Evaluating Effect of Meta-analysis of RCTs Evaluating Effect of Orlistat Therapy on Weight Loss at 1-YearOrlistat Therapy on Weight Loss at 1-Year
Study or Sub-category
WMD (random)95% CI
Hollander 1998*
Sjostrom 1998
Davidson 1999
Finer 2000
Heuptman 2000
Lindgarde 2000
Rossner 2000
Bakris 2002
Broom 2002
Kelley 2002*
Miles 2002*
Total (95% CI)
Padwal et al. Int J Obes 2003;27:1437
*All subjects had type 2 diabetesWMD=weighted mean difference Favours
TreatmentFavoursControl
-10 -5 0 105
Slide Source:www.obesityonline.org
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Independent Effect of Orlistat on Plasma Independent Effect of Orlistat on Plasma LDL-CholesterolLDL-Cholesterol
Weight Loss Category (%initial body weight)
Change inPlasma
LDL-Cholesterol
Concentration(mmol/L)
Segal et al. FASEB J. 1999;13:A873.
*P < 0.01 vs placebo. Data pooled from 5 trials (N = 1773).
0 - 5 5 – 10 10 – 15 >15
Placebo
Orlistat
** *
*
Slide Source:www.obesityonline.org
0
10
20
30
40
50
60
Orlistat Inhibits Dietary Cholesterol Orlistat Inhibits Dietary Cholesterol AbsorptionAbsorption
Ch
ole
ste
rol A
bso
rbed
(%
ing
est
ed
)
*P<0.05 vs baseline.
Mittendorfer et al. Obes Res 2001;9:599.
Baseline Orlistat
*
Slide Source:www.obesityonline.org
Gastrointestinal Side Effects of Orlistat TherapyGastrointestinal Side Effects of Orlistat Therapy
Year 1 Year 2Placebo Orlistat Placebo Orlistat
Fatty/oily stool 5 31 1 8
Increased defecation 7 20 2 2
Liquid stools 10 13 5 8
Fecal urgency 3 10 2 3
Flatulence 3 7 2 3
Flatus with discharge 0 7 0 1
Fecal incontinence 0 7 0 2
Oily evacuation 1 6 0 5
Low plasma vitamin conc:
Vitamin A 0.6 0.3 0.8 0
Vitamin D 0.6 5.1 0.8 3.1
Vitamin E 0.9 4.6 0 1.6
Sjostrom et al. Lancet 1998;352:167.
Values are percentage of subjects.
Slide Source:www.obesityonline.org
0
50
100
150
200
250
Case Report of Effect of Orlistat on Case Report of Effect of Orlistat on Blood Cyclosporin A ConcentrationBlood Cyclosporin A Concentration
Blo
od
Cyc
losp
ori
n A
Co
nce
ntr
atio
n (
ng
/mL
)
Le Beller et al. Transplantation 2000;70:1541.
Time (d)
0 100 200 300 400
Orlistat StartOrlistat StartSwitch to Switch to
NeoralNeoral
Slide Source:www.obesityonline.org
FDA Approved Orlistat 60mg for FDA Approved Orlistat 60mg for Non-Prescription Use on February 7, 2007Non-Prescription Use on February 7, 2007 Trade name: allī
For weight loss
In overweight adults
With reduced-calorie, low-fat diet
One capsule with each meal containing fat
Slide Source:www.obesityonline.org
The OTC Orlistat Product Will Provide The OTC Orlistat Product Will Provide Both Medication and Behavioral SupportBoth Medication and Behavioral Support
Behavioral Support: Welcome Guide
Companion Guide
QuickFact Cards
Healthy Eating Guide
Calorie and Fat Counter
Daily Journal
Online 12-month Support Program
Compliance shuttle
Slide Source:www.obesityonline.org
Orlistat 60mg + Diet: Significantly More Orlistat 60mg + Diet: Significantly More Effective Than Placebo + DietEffective Than Placebo + Diet
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
% c
ha
ng
e f
rom
bas
elin
e
Placebo
60 mg tid
120 mg tid
Treatment weekSignificant relative weight change from baseline at 6 months for 60 mg vs. placebo and 120 mg vs. placebo, P<0.001 - ITT population, observed data; mean +/-- SE
Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006
Slide Source:www.obesityonline.org
Orlistat 60 mg vs. 120 mgOrlistat 60 mg vs. 120 mg
Fewer GI events with 60 mg dose
Significantly lower chance of GI events in first four weeks of treatment
One third fewer GI events within first week
Lower withdrawal rate due to GI events
Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006
Slide Source:www.obesityonline.org
Undesired GI Effects Result from Undesired GI Effects Result from Meals with More than 15-20 Grams of FatMeals with More than 15-20 Grams of Fat
6 Months
Placebo 60 mg tid 120 mg tid
Adverse event N=634 N=623 N=632
Fecal urgency 7.9% 18.8% 23.4%
Oily spotting 1.1% 17.7% 21.7%
Flatus with discharge 1.9% 17.3% 19.9%
Fatty/Oily stool 2.7% 17.2% 21.7%
Oily evacuation 0.6% 11.6% 13.4%
Increased defecation 2.7% 7.1% 8.2%
Fecal incontinence 0.8% 4.7% 7.8%
* Significantly different 60 mg compared 120 mg (p<0.05)
*
*
*
*
Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006
Slide Source:www.obesityonline.org
Multi-Vitamin Supplement Multi-Vitamin Supplement Recommended with Orlistat TherapyRecommended with Orlistat Therapy
* Significant difference between 60-mg and 120-mg doses; Fisher’s Exact Test at p<0.05
This analysis includes all U.S. Studies (NM14336, NM14161, and NM14185) conducted by Roche of orlistat 60 and 120 mg that did not require routine vitamin supplementation
Placebo (%) 60 mg tid (%) 120 mg tid (%)
Vitamin A 3/580 (0.5) 1/203 (0.5) 15/962 (1.6)
Vitamin D 13/558 (2.3) 2/209 (1.0)* 50/954 (5.2)
Vitamin E 2/565 (0.4) 7/196 (3.6) 29/944 (3.1)
Beta-carotene 2/576 (0.3) 3/207 (1.4) 40/977 (4.1)
Rate of 2 Consecutive Below-Normal Vitamin Levels in 6 Months of Treatment
Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006
Slide Source:www.obesityonline.org
Undesired GI Effects Result from Undesired GI Effects Result from Meals with More than 15-20 Grams of FatMeals with More than 15-20 Grams of Fat
6 Months
Placebo 60 mg tid 120 mg tid
Adverse event N=634 N=623 N=632
Fecal urgency 7.9% 18.8% 23.4%
Oily spotting 1.1% 17.7% 21.7%
Flatus with discharge 1.9% 17.3% 19.9%
Fatty/Oily stool 2.7% 17.2% 21.7%
Oily evacuation 0.6% 11.6% 13.4%
Increased defecation 2.7% 7.1% 8.2%
Fecal incontinence 0.8% 4.7% 7.8%
* Significantly different 60 mg compared 120 mg (p<0.05)
*
*
*
*
Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006
Slide Source:www.obesityonline.org
Multi-Vitamin Supplement Multi-Vitamin Supplement Recommended with Orlistat TherapyRecommended with Orlistat Therapy
* Significant difference between 60-mg and 120-mg doses; Fisher’s Exact Test at p<0.05
This analysis includes all U.S. Studies (NM14336, NM14161, and NM14185) conducted by Roche of orlistat 60 and 120 mg that did not require routine vitamin supplementation
Placebo (%) 60 mg tid (%) 120 mg tid (%)
Vitamin A 3/580 (0.5) 1/203 (0.5) 15/962 (1.6)
Vitamin D 13/558 (2.3) 2/209 (1.0)* 50/954 (5.2)
Vitamin E 2/565 (0.4) 7/196 (3.6) 29/944 (3.1)
Beta-carotene 2/576 (0.3) 3/207 (1.4) 40/977 (4.1)
Rate of 2 Consecutive Below-Normal Vitamin Levels in 6 Months of Treatment
Source: FDA Advisory Committee Review of orlistat 60mg OTC, Jan 23, 2006
Slide Source:www.obesityonline.org
Even Small Weight Losses Have Even Small Weight Losses Have Positive Impact on Risk FactorsPositive Impact on Risk Factors
HbA1c
HDL cholesterol
Blood pressure
Triglycerides
Total cholesterol
5%-10% Weight Loss
~5% Weight Loss
1. Wing RR et al. Arch Intern Med. 1987;147:1749-1753.2. Mertens IL, Van Gaal LF. Obes Res. 2000;8:270-278.3. Blackburn G. Obes Res. 1995;3(Suppl 2):211S-216S.4. Ditschunheit HH et al. Eur J Clin Nutr. 2002;56:264-270.
1
2
3
3
--
1
2
3
3
4
Slide Source:www.obesityonline.org
Sibutramine Blocks Neuronal Monoamine Sibutramine Blocks Neuronal Monoamine (Serotonin, Norepinephrine, Dopamine) Reuptake(Serotonin, Norepinephrine, Dopamine) Reuptake
XXXX
= Monoamine
S
S = Sibutramine
Slide Source:www.obesityonline.org
-10
-8
-6
-4
-2
0
Effect of Continuous vs Intermittent Sibutramine Effect of Continuous vs Intermittent Sibutramine Therapy on Body WeightTherapy on Body Weight
Bod
y W
eigh
t C
hang
e (k
g)
Wirth and Krause. JAMA 2001;286:1331.
Sibutramine dose=15 mg/d.Time (wk)
0 4 8 12 16 20 24 28 32 36 40 44 48
PlaceboPlaceboIntermittent sibutramineIntermittent sibutramineContinuous sibutramineContinuous sibutramine
Run-inperiod
Slide Source:www.obesityonline.org
Weight Loss
195
200
205
210
215
220
225
230
Initial Responders to Sibutramine Can Initial Responders to Sibutramine Can Maintain Long-term Weight LossMaintain Long-term Weight Loss
James et al. Lancet 2000:356:2119.
Randomization at 6 months in those with >5% weight loss.
Bod
y W
eigh
t (lb
.)
Month20 64 108 1412 1816 20 22 24
Placebo
Sibutramine 10-20 mg/d
Weight Maintenance
Slide Source:www.obesityonline.org
-8
-6
-4
-2
0
Use of Sibutramine within a Health Maintenance Use of Sibutramine within a Health Maintenance Organization Enhances Weight LossOrganization Enhances Weight Loss
0Weeks
Porter et al. Am J Manag Care 2004;10:369
Wei
ght C
hang
e (k
g)
26 52
No drug therapy
Sibutramine therapy
Slide Source:www.obesityonline.org
Meta-analysis of RCTs Evaluating Effect of Meta-analysis of RCTs Evaluating Effect of Sibutramine Therapy on Weight Loss at 1-YearSibutramine Therapy on Weight Loss at 1-Year
Study or Sub-category
WMD (random)95% CI
McMahon 2000
Smith 2001
McMahon 2002 *
Total (95% CI)
Padwal et al. Int J Obes 2003;27:1437
•All subjects had hypertensionWMD=weighted mean difference
-10Favours
TreatmentFavoursControl
-5 0 105
Slide Source:www.obesityonline.org
Adverse Effects of Sibutramine TherapyAdverse Effects of Sibutramine Therapy
Subjects (%)Adverse Effect Placebo Sibutramine
Headache 18.6 30.3
Dry mouth 4.2 17.2
Constipation 6.0 11.5
Insomnia 4.5 10.7
Dizziness 3.4 7.0
Hypertension 0.9 2.1
Tachycardia 0.6 2.6
Palpitation 0.8 2.0Meridia™ Package Insert, 2001.
Slide Source:www.obesityonline.org
Blood Pressure and Pulse Rate After 1 Year Sibutramine Blood Pressure and Pulse Rate After 1 Year Sibutramine Therapy in Patients with Controlled HypertensionTherapy in Patients with Controlled Hypertension
Placebo Sibutramine
Systolic BP change(mm Hg)
+1.5 +2.7
Diastolic BP change(mm Hg)
-1.3 +2.0 *
Pulse rate change(beats/min)
0 4.9 *
Withdrawal due tohypertension (% subjects)
1.4 5.3
McMahon et al. Arch Intern Med 2000;160:2185.*P<0.05 vs placebo.
Slide Source:www.obesityonline.org
-25
-20
-15
-10
-5
0
Additive Effects of Behavior and Diet Therapy with Additive Effects of Behavior and Diet Therapy with Pharmacotherapy for ObesityPharmacotherapy for Obesity
We
igh
t Ch
an
ge
(%
)
Wadden et al. Arch Intern Med 2001;161:218.
*P<0.05 vs medication alone.Time (months)
0 2 4 8 12106
Medication alone
Medication and behaviormodification
Medication, behaviormodification and meal
replacements
*
*
Slide Source:www.obesityonline.org
Bariatric Surgery In the Management of Bariatric Surgery In the Management of ObesityObesity
Slide Source:www.obesityonline.org
Obese Patients Have Unrealistic Weight Obese Patients Have Unrealistic Weight Loss GoalsLoss Goals
Outcome Weight (lbs) % Reduction
Initial 218 0
Dream 135 38
Happy 150 31
Acceptable 163 25
Disappointed 180 17
Foster et al. J Consult Clin Psychol 1997;65:79.
Slide Source:www.obesityonline.org
Obesity Treatment PyramidObesity Treatment Pyramid
DietDiet Physical ActivityPhysical Activity
Lifestyle ModificationLifestyle Modification
PharmacotherapyPharmacotherapy
SurgerySurgery
Slide Source:www.obesityonline.org
Guide for Selecting Obesity TreatmentGuide for Selecting Obesity Treatment
The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No.00-4084
Treatment 25-26.9 27-29.9 30-34.9 35-39.9 >40
Diet, Exercise, Behavior Tx
+ + + + +
Pharmaco-therapy
With co-morbidities + + +
SurgeryWith co-
morbidities +
BMI Category (kg/mBMI Category (kg/m22))
Slide Source:www.obesityonline.org
What Operations are Performed?What Operations are Performed?
Restrictive Surgeries-limit amount of food held by a surgically created smaller gastric pouch and slow gastric emptying
1.) Vertical Banded Gastroplasty (VBG)
2.) Laparoscopic Adjustable Silicone Gastric banding (LASGB)
Slide Source:www.obesityonline.org
What Operations are Performed?What Operations are Performed?
Restrictive Malabsorbtive-gastric restriction combined with selective malabsorbtion
1.) Roux-en-Y Gastric Bypass (RYGB)
The most commonly performed proc.
2.) Biliopancreatic Diversion (BPD) or Biliopancreatic Diversion with Duodenal Switch (BPDDS)
Slide Source:www.obesityonline.org
What are The Operative Results?What are The Operative Results?
30-35% weight loss in 12-18 months
Roux-en-Y Gastric bypass the most widely accepted and best results
Higher volume centers and surgeons have best results. Still risk and complications
10 year weight loss maintenance best with surgery
Slide Source:www.obesityonline.org
Treatment of the Metabolic Syndrome in Treatment of the Metabolic Syndrome in Overweight or Obese PatientsOverweight or Obese Patients
• Weight loss induced by diet and increased physical activity is the cornerstone of therapy
• Weight loss induced by drug therapy can also improve specific features of the metabolic syndrome
• Bariatric surgery is the most effective weight loss therapy for extremely obese subjects and improves all features of the metabolic syndrome
Slide Source:www.obesityonline.org
ConclusionsConclusions
Obesity is a chronic disease
Modest weight loss (5% -10% of body weight) can have considerable medical benefits
Lifestyle change (diet and physical activity) is the cornerstone of therapy
Pharmacotherapy can be useful in properly selected patients
Bariatric surgery is the most effective therapy for obesity
Slide Source:www.obesityonline.org
Obesity-Related ResourcesObesity-Related ResourcesProfessional AssociationsProfessional Associations
North American Association for the Study of Obesity (NAASO)
American Academy of Family Physicians (AAFP)
American College of Sports Medicine (ACSM)
American Diabetes Association (ADA)
American Dietetic Association (ADA)
American Gastroenterological Association (AGA)
American Heart Association (AOA)
American Obesity Association (AOA)
American Society for Bariatric Surgery (ASBS)
www.naaso.org
www.aafp.org
www.acsm.org
www.diabetes.org
www.eatright.org
www.gastro.org
www.americanheart.org
www.obesity.org
www.asbs.org