the efficacy of pharmaceutical and surgical approaches to weight loss

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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


Principles of Pharmacotherapy Principles of Pharmacotherapy in the Management of Obesityin the Management of Obesity


Drugs Approved by FDA for Treating ObesityDrugs Approved by FDA for Treating Obesity

Generic NameTrade

NamesDEA

ScheduleApproved

UseYear

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


-32-28-24-20-16-12-8-40

Effect of Continuous and Intermittent Effect of Continuous and Intermittent Phentermine Therapy on Body WeightPhentermine Therapy on Body Weight

0Time (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


Drugs Approved by FDA for Treating ObesityDrugs Approved by FDA for Treating Obesity

Generic NameTrade

NamesDEA

ScheduleApproved

UseYear

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


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

LIPASELIPASELIPASELIPASE

Bile AcidsBile AcidsMicelleMicelle

MGMGFAFA


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.

Feca

l Fat

Exc

retio

n (%

inta

ke)

Orlistat Daily Dose (mg)0 200 400 600 800 1000 1200


-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


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 1998Davidson 1999Finer 2000Heuptman 2000Lindgarde 2000Rossner 2000Bakris 2002Broom 2002Kelley 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


-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

** *

*


0

10

20

30

40

50

60

Orlistat Inhibits Dietary Cholesterol Orlistat Inhibits Dietary Cholesterol AbsorptionAbsorption

Cho

lest

erol

Abs

orbe

d (%

inge

sted

)

*P<0.05 vs baseline.Mittendorfer et al. Obes Res 2001;9:599.

Baseline Orlistat

*


Gastrointestinal Side Effects of Orlistat TherapyGastrointestinal Side Effects of Orlistat TherapyYear 1 Year 2

Placebo Orlistat Placebo OrlistatFatty/oily stool 5 31 1 8Increased defecation 7 20 2 2Liquid stools 10 13 5 8Fecal urgency 3 10 2 3Flatulence 3 7 2 3Flatus with discharge 0 7 0 1Fecal incontinence 0 7 0 2Oily evacuation 1 6 0 5Low 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.


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 C

yclo

spor

in A

Con

cent

ratio

n (n

g/m

L)

Le Beller et al. Transplantation 2000;70:1541.

Time (d)0 100 200 300 400

Orlistat StartOrlistat StartSwitch to Switch to

NeoralNeoral


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


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


Orlistat 60mg + Diet: Significantly More Orlistat 60mg + Diet: Significantly More Effective Than Placebo + DietEffective Than Placebo + Diet

-10-9-8-7-6-5-4-3-2-10

0 4 8 12 16 20 24 28 32 36 40 44 48 52

% c

hang

e fr

om b

asel

ine

Placebo60 mg tid120 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


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



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)

*

*

*

*



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<0.05This 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



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)

*

*

*

*



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<0.05This 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



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


Sibutramine Blocks Neuronal Monoamine Sibutramine Blocks Neuronal Monoamine (Serotonin, Norepinephrine, Dopamine) Reuptake(Serotonin, Norepinephrine, Dopamine) Reuptake

XX

= Monoamine

S

S = Sibutramine


-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 Cha

nge

(kg)

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


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


-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


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


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.


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.


-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

Wei

ght C

hang

e (%

)

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

*

*


Bariatric Surgery In the Management of Bariatric Surgery In the Management of ObesityObesity


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.


Obesity Treatment PyramidObesity Treatment Pyramid

DietDiet Physical ActivityPhysical Activity

Lifestyle ModificationLifestyle Modification

PharmacotherapyPharmacotherapy

SurgerySurgery


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))


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)


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)


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


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


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


Obesity-Related ResourcesObesity-Related ResourcesProfessional AssociationsProfessional AssociationsNorth 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

the efficacy of pharmaceutical and surgical approaches to weight loss

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