The Efficacy of Pharmaceutical and Surgical Approaches to weight loss

1
The Efficacy of Pharmaceutical and Surgical
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

2
Principles of Pharmacotherapy in the Management
of Obesity
3
Drugs Approved by FDA for Treating Obesity
Generic Name Trade 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
Phentermine Adipex, lonamin IV Short-term 1973
Phendimetrazine Bontril, Prelu-2 III Short-term 1961
Benzphetamine Didrex III Short-term 1960
4
Effect of Continuous and Intermittent Phentermine
Therapy on Body Weight
Continuous Dummy
Weight Loss (lbs)
ContinuousPhentermine
Alternate Phentermine and Dummy
0
8
24
28
36
4
12
16
20
32
Time (weeks)
Munro JF et al. Brit Med J 1352, 1968
5
Drugs Approved by FDA for Treating Obesity
Generic Name Trade 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
Phentermine Adipex, lonamin IV Short-term 1973
Phendimetrazine Bontril, Prelu-2 III Short-term 1961
Benzphetamine Didrex III Short-term 1960
6
Orlistat Prevents Fat Digestion and Absorption by
Binding to Gastrointestinal Lipases
Mucosal Cell
Intestinal Lumen
LIPASE
LIPASE
TG
Orlistat
FA
MG
LIPASE
Bile Acids
Micelle
TGtriglyceride MGmonoglyceride FAfatty acid.
7
Effect of Orlistat Dose on Fecal Fat Excretion
Fecal Fat Excretion ( intake)
0
200
400
600
800
1000
1200
Orlistat Daily Dose (mg)
Zhi et al. Clin Pharmacol Ther 19945682.
8
Effect of Long-term Orlistat Therapy on Body
Weight
-4.1 kg
Placebo
Change in Weight (kg)
-6.9 kg
Orlistat
Plt0.001 vs placebo
0
52
104
156
208
Weeks
Torgenson et al. Diabetes Care 200427155
9
Meta-analysis of RCTs Evaluating Effect of
Orlistat 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)
All subjects had type 2 diabetes WMDweighted
mean difference
-10
-5
0
10
5
FavoursTreatment
FavoursControl
Padwal et al. Int J Obes 2003271437
10
Independent Effect of Orlistat on Plasma
LDL-Cholesterol
Change inPlasmaLDL-CholesterolConcentration(mm
ol/L)




0 - 5
5 10
10 15
gt15
Weight Loss Category (initial body weight)
P lt 0.01 vs placebo. Data pooled from 5 trials
(N 1773).
Segal et al. FASEB J. 199913A873.
11
Orlistat Inhibits Dietary Cholesterol Absorption

Cholesterol Absorbed ( ingested)
Baseline
Orlistat
Plt0.05 vs baseline.
Mittendorfer et al. Obes Res 20019599.
12
Gastrointestinal Side Effects of Orlistat Therapy
Year 1 Year 1 Year 2 Year 2
Placebo 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
Values are percentage of subjects.
Sjostrom et al. Lancet 1998352167.
13
Case Report of Effect of Orlistat on Blood
Cyclosporin A Concentration
Orlistat Start
Switch to Neoral
Blood Cyclosporin AConcentration (ng/mL)
0
100
200
300
400
Time (d)
Le Beller et al. Transplantation 2000701541.
14
FDA Approved Orlistat 60mg for Non-Prescription
Use on February 7, 2007

• Trade name alli
• For weight loss
• In overweight adults
• With reduced-calorie, low-fat diet
• One capsule with each meal containing fat

15
The OTC Orlistat Product Will Provide Both
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

16
Orlistat 60mg Diet Significantly More
Effective Than Placebo Diet
0
Placebo
-1
-2
-3
-4
-5
change from baseline
-6
-7
-8
-9
-10
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Treatment week
Significant relative weight change from baseline
at 6 months for 60 mg vs. placebo and 120 mg vs.
placebo, Plt0.001 - ITT population, observed data
mean /-- SE
Source FDA Advisory Committee Review of orlistat
60mg OTC, Jan 23, 2006
17
Orlistat 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
18
Undesired GI Effects Result from Meals with More
than 15-20 Grams of Fat
6 Months 6 Months 6 Months
Placebo 60 mg tid 120 mg tid
Adverse event N634 N623 N632
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
(plt0.05)
Source FDA Advisory Committee Review of orlistat
60mg OTC, Jan 23, 2006
19
Multi-Vitamin Supplement Recommended with
Orlistat Therapy
Rate of 2 Consecutive Below-Normal Vitamin
Levels in 6 Months of Treatment
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)
Significant difference between 60-mg and 120-mg
doses Fishers Exact Test at plt0.05 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
Source FDA Advisory Committee Review of orlistat
60mg OTC, Jan 23, 2006
20
Undesired GI Effects Result from Meals with More
than 15-20 Grams of Fat
6 Months 6 Months 6 Months
Placebo 60 mg tid 120 mg tid
Adverse event N634 N623 N632
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
(plt0.05)
Source FDA Advisory Committee Review of orlistat
60mg OTC, Jan 23, 2006
21
Multi-Vitamin Supplement Recommended with
Orlistat Therapy
Rate of 2 Consecutive Below-Normal Vitamin
Levels in 6 Months of Treatment
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)
Significant difference between 60-mg and 120-mg
doses Fishers Exact Test at plt0.05 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
Source FDA Advisory Committee Review of orlistat
60mg OTC, Jan 23, 2006
22
Even Small Weight Losses Have Positive Impact on
Risk Factors
5-10 Weight Loss
5 Weight Loss
1
1
HbA1c
Blood pressure
2
2
Total cholesterol
3
3
HDL cholesterol
3
3
Triglycerides
--
4
1. Wing RR et al. Arch Intern Med.
19871471749-1753. 2. Mertens IL, Van Gaal LF.
Obes Res. 20008270-278. 3. Blackburn G. Obes
Res. 19953(Suppl 2)211S-216S. 4. Ditschunheit
HH et al. Eur J Clin Nutr. 200256264-270.
23
Sibutramine Blocks Neuronal Monoamine (Serotonin,
Norepinephrine, Dopamine) Reuptake
X
S
S
Monoamine
Sibutramine
24
Effect of Continuous vs Intermittent Sibutramine
Therapy on Body Weight
Placebo Intermittent sibutramine Continuous
sibutramine
Body Weight Change (kg)
Run-in period
0
4
8
12
16
20
24
28
32
36
40
44
48
Time (wk)
Sibutramine dose15 mg/d.
Wirth and Krause. JAMA 20012861331.
25
Initial Responders to Sibutramine Can Maintain
Long-term Weight Loss
Weight Loss
Weight Maintenance
Placebo Sibutramine 10-20 mg/d
Body Weight (lb.)
2
0
6
4
10
8
14
12
18
16
20
22
24
Month
Randomization at 6 months in those with gt5
weight loss.
James et al. Lancet 20003562119.
26
Use of Sibutramine within a Health Maintenance
Organization Enhances Weight Loss
No drug therapy
Weight Change (kg)
Sibutramine therapy
0
26
52
Weeks
Porter et al. Am J Manag Care 200410369
27
Meta-analysis of RCTs Evaluating Effect of
Sibutramine Therapy on Weight Loss at 1-Year
Study or Sub-category WMD (random)95 CI
McMahon 2000
Smith 2001
McMahon 2002
Total (95 CI)

• All subjects had hypertension
• WMDweighted mean difference

Padwal et al. Int J Obes 2003271437
28
Adverse Effects of Sibutramine Therapy
Subjects () Subjects () Subjects () Subjects ()
Adverse Effect Placebo Sibutramine Sibutramine
Headache 18.6 18.6 30.3
Dry mouth 4.2 4.2 17.2
Constipation 6.0 6.0 11.5
Insomnia 4.5 4.5 10.7
Dizziness 3.4 3.4 7.0
Hypertension 0.9 0.9 2.1
Tachycardia 0.6 0.6 2.6
Palpitation 0.8 0.8 2.0
Meridia Package Insert, 2001.
29
Blood Pressure and Pulse Rate After 1 Year
Sibutramine Therapy 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
Plt0.05 vs placebo.
McMahon et al. Arch Intern Med 20001602185.
30
Additive Effects of Behavior and Diet Therapy
with Pharmacotherapy for Obesity
Medication alone
Medication and behaviormodification

Weight Change ()

Medication, behaviormodification and meal
replacements
0
2
4
8
12
10
6
Time (months)
Plt0.05 vs medication alone.
Wadden et al. Arch Intern Med 2001161218.
31
Bariatric Surgery In the Management of Obesity
32
Obese Patients Have Unrealistic Weight Loss 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 19976579.
33
Obesity Treatment Pyramid
34
Guide for Selecting Obesity Treatment
BMI Category (kg/m2)
Treatment 25-26.9 27-29.9 30-34.9 35-39.9 gt40
Diet, Exercise, Behavior Tx
Pharmaco-therapy With co-morbidities
Surgery With co-morbidities
The Practical Guide Identification, Evaluation,
and Treatment of Overweight and Obesity in
Adults. October 2000, NIH Pub. No.00-4084
35
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)

36
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)

37
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

38
Treatment of the Metabolic Syndrome in Overweight
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

39
Conclusions

• 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

40
Obesity-Related ResourcesProfessional
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.diabe
tes.org www.eatright.org www.gastro.org www.americ
anheart.org www.obesity.org www.asbs.org