obesity treatment pyramid

Slide Source:www.obesityonline.org

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))


Obesity and Dietary Therapy Obesity and Dietary Therapy “Duct Tape”“Duct Tape”


-20

-15

-10

-5

0

5

Short-term Obesity Therapy Does Not Short-term Obesity Therapy Does Not Result in Long-term Weight LossResult in Long-term Weight Loss

Cha

nge

in W

eigh

t (kg

)

Wadden et al. Int J Obes 1989;13 (Suppl 2):39.

5-yearFollow-up

1-yearFollow-up

End ofTreatment

Baseline

Diet alone

Behavior therapy

Combined therapy


-35

-30

-25-20

-15

-10-5

0No Active TreatmentActive Treatment

Sustained Weight Loss Can Be Achieved Sustained Weight Loss Can Be Achieved with Behavior Modification Therapywith Behavior Modification Therapy

0Years

2 4 6

Men

Björvell and Rössner. Int J Obes Relat Metab Disord 1992;16:623.

Wei

ght L

oss

(kg)

8 10-12

Women


Cardinal Behaviors of Successful Long-term Cardinal Behaviors of Successful Long-term Weight ManagementWeight ManagementNational Weight Control Registry DataNational Weight Control Registry Data Self-monitoring:

– Diet: record food intake daily, limit certain foods or food quantity

– Weight: check body weight >1 x/wk Low-calorie, low-fat diet:

– Total energy intake: 1300-1400 kcal/d– Energy intake from fat: 20%-25%

Eat breakfast daily Regular physical activity: 2500-3000 kcal/wk

(eg, walk 4 miles/d)Klem et al. Am J Clin Nutr 1997;66:239. McGuire et al.Int J Obes Relat Metab Disord 1998;22:572.


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


Regulation of Food IntakeRegulation of Food IntakeBrainBrain

NPYAGRPgalanin

Orexin-ADynorphinECS/CB1

StimulateStimulateα-MSHCRH/UCNGLP-I

CARTNE5-HT

InibitInibitCentral SignalsCentral Signals

GlucoseCCK, GLP-1,Apo-A-IVVagal afferentsInsulinGhrelin

Leptin

Cortisol

Peripheral signalsPeripheral signals Peripheral organsPeripheral organs

+

+

Gastrointestinaltract

Adiposetissue

FoodIntake

Adrenal glands

External factorsEmotions, DrugsFood characteristicsLifestyle behaviorsEnvironmental cues


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


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


-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


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.


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


-10

-8

-6

-4

-2

0

Effect of Continuous vs Intermittent Subutramine Effect of Continuous vs Intermittent Subutramine 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


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.


-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 QOM

ContinuousPhentermine

Continuous Dummy


Regulation of Food IntakeRegulation of Food IntakeBrainBrain

NPYAGRPgalanin

Orexin-ADynorphinECS/CB1

StimulateStimulateα-MSHCRH/UCNGLP-I

CARTNE5-HT

InibitInibitCentral SignalsCentral Signals

GlucoseCCK, GLP-1,Apo-A-IVVagal afferentsInsulinGhrelin

Leptin

Cortisol

Peripheral signalsPeripheral signals Peripheral organsPeripheral organs

+

+

Gastrointestinaltract

Adiposetissue

FoodIntake

Adrenal glands

External factorsEmotions, DrugsFood characteristicsLifestyle behaviorsEnvironmental cues


Modified from Marx, Science 2003 February 7; 299: 846-849. (in News)

Gastrointestinal Peptides HormonesGastrointestinal Peptides Hormones

food intake regulation

digestion and metabolism

Anti-obesity potential

Anti-diabetes potential

Vagusnerve

Ghrelin

InsulinAmylin

Glucagon

Leptin

PYY

GLP-1CCK


GLP-1GLP-1 GLP-1: incretin hormone

Exenatide (Byetta); incretin mimetic– Enhances insulin secretion– Suppresses elevated glucagon secretion– Reduces food intake and body weight– Slows gastric emptying– Increase in beta-cell mass

Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001; 86:3717-3723Drucker DJ. Mol Endocrinol 2003; 17:161-171Nielsen LL, et al. Reg Pept 2004; 117:77-88

Neuroendocrinology of Food Intake RegulationHindbrain as a Target for Peripheral Satiety Signals

Modified from Marx, Science 2003 February 7; 299: 846-849. (in News)

LeptinInsulin

PYYGhrelinGI tract

Spinalnerves

VagusCCK

Hypothalamus ARC

NTS/AP

Area Postrema:• part of dorsal vagal complex• chemoreceptive (no BBB)• site of neural integration

• bi-directional projections to the GI tract (via vagal afferents and efferents)

• bi-directional projections to the hypothalamus, amygdala and other regions

Amylin other circulating gut peptides


Safety and Tolerability Safety and Tolerability Exenatide Open-Label ExtensionsExenatide Open-Label Extensions Exenatide generally well tolerated Adverse events

– Nausea (30-40%) – Diarrhea (7%)– Vomiting (9%)– Feeling jittery (5%)– Dizziness (3%)– Headache (3%)

Amylin Binding Sites in the Brain

Amylin:A Neuroendocrine Hormone

Amylin ReceptorIdentified

CC

N N

RAMP1 or 3

CTR

Dorsale Raphe

Nucleus Accumbens Area Postrema

Beaumont K, et al. Mol Pharm 1993; 44:493-497Adapted from Muff R, et al. Endocrinology1999; 140:2924-2927

Effects of Pramlintide in Type 2 Diabetes

-3.0-2.5-2.0-1.5-1.0-0.5

00.51.01.52.02.5

Week 4 Week 13 Week 26

Pooled 120 µg BID Pramlintide Intent to Treat Populations

-3

-2

-1

0

1

2

3

4

5

6Week 4 Week 13 Week 26Week 4 Week 13 Week 26

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

-0.8

Data on file, Amylin Pharmaceuticals, Inc.

Placebo + Insulin (N=284; Baseline A1C 9.3%)120 µg Pramlintide BID Dose + Insulin (N=292;Baseline A1C 9.1%)

Placebo + Insulin120 µg Pramlintide

Change in Insulin Use (%)Change in A1C (%) Change in Weight (lb)


Energy Balance Feeding Behavior Gastric emptying

GI motility

Hepatic glucose output Lipogenesis

Hepatic LipogenesisAdipose Tissue Metabolism

Glucose HomeostasisGlucose uptake

Glucose, lipid oxidation

LipolysisLipogenesis

Ghrelin, PYY

Limbic forebrainMotivation for palatable food

HypothalamusHunger/satiety

Endocannabinoid System (CB-1) as a Potential Target of Endocannabinoid System (CB-1) as a Potential Target of Action for Modulation of Energy Homeostasis and Obesity Action for Modulation of Energy Homeostasis and Obesity

27


The ECS is Overactivated in:The ECS is Overactivated in:

28

Animal models of genetic obesity

Animal models of diet-induced obesity

Human obesity


Endocannabinoids Stimulate Endocannabinoids Stimulate Food Intake in MiceFood Intake in Mice

Hao S et al. Eur J Pharmacology. 2000; 392:147-156.

Anandamide 0.001 mg/kg

Vehicle

*P<0.05; **P<0.01 vs vehicle

1 3 5 7 Day

Food intake (grams/day)

7

6

5

4

3

*

*

*

**

29


Engeli S, et al. Diabetes 2005; 54:2838–2843.

* P<0.05 vs lean women

The ECS is Upregulated in Human Obesity30


10

8

6

4

2

0

16

14

12

10

8

5

4

18.5-24.9 25.0-29.9 >30.0

BMI (kg/m2)

18.5-24.9 25.0-29.9 >30.0

Caucasians African Americans

P<0.05*P<0.01* P<0.05*

BMI (kg/m2)

Percent of subjects with FAAH 385 A/A genotype by BMI category Percent of subjects with FAAH 385 A/A genotype by BMI category

% o

f sub

ject

s w

ith F

AA

H 3

85 A

/A * vs normal BMI

A Mutation in the Enzyme That Degrades Endocannabinoids is Associated with Increased BMI

Sipe JC et al. Int J Obes Relat Metab Disord.2005;29:755-759.

31


CBCB11 Blockade Produces a Dose-Related R Blockade Produces a Dose-Related Reducteduction in ion in Food Intake in MiceFood Intake in Mice

Wiley JL et al. Br J Pharmacol. 2005;145:293-300.

2.0

1.5

1.0

0.5

0.00.0 0.3 1.0 3.0 10.0 Rimonabant Dose (mg/kg-1)

Food intake

(g)

32


Adipose tissue metabolism– EC stimulation with CB1 agonist increases adipose

tissue LPL expression while CB1 blockade inhibits this effect

– CB1 stimulation reduces while blockade increases adiponectin synthesis

– CB1 blockade reverses the histological changes in adipose tissue produced by diet-induced obesity

– EC stimulation reduces the expression of AMP kinase in visceral fat

Supporting Evidence:Supporting Evidence:33

Cota D et al. J Clin Invest. 2003;112:423. Matias I, et al. XV ICRS Symposium June 24-27, 2005; Clearwater, Fla. Jbilo O, et al. FASEB J. 2005;19:1567-1569.


The Peripheral ECS in Adipose TissueThe Peripheral ECS in Adipose Tissue

Adipose tissue of obese mice fed a high fat diet (HFD) plus rimonabant resembles that of lean mice fed a standard diet (STD)

Jbilo O, et al. FASEB J. 2005;19:1567-1569.

34

Standard Diet

High Fat Diet

High Fat Diet + Rimonabant


ECS Stimulation, Centrally and Peripherally, ECS Stimulation, Centrally and Peripherally, Favors Metabolic Processes that Lead to:Favors Metabolic Processes that Lead to:

35

Weight Gain Lipogenesis Insulin Resistance Dyslipidemia Impaired Glucose Homeostasis


RIO: Rimonabant In Overweight/ObesityRIO: Rimonabant In Overweight/ObesityCB-1 Blockade in Human StudiesCB-1 Blockade in Human Studies

(>6600 patients enrolled)

Pi-Sunyer FX.Obes Res. 2004;12(suppl):08-OR, A27.

1

1 year1047Obese or overweight with type 2 diabetes

1 year1033Obese or overweight withuntreated dyslipidemia(excluding diabetes)

2 years1507Obese or overweightwith/without comorbidities(excluding diabetes)

1+1 yearRe

3040Obese or overweightwith/without comorbidities(excluding diabetes)

DesignPopulationStudy

1 yearObese or overweight with type 2 diabetes

yearObese or overweight withuntreated(excluding diabetes)

2 yearsObese or overweightwith/without comorbidities(excluding diabetes)

1+1 yearRerandomized

Obese or overweightwith/without comorbidities(excluding diabetes)

N=6627

36


RIO-Europe and RIO-Lipids:RIO-Europe and RIO-Lipids: Weight Change at 1 Year Weight Change at 1 Year

Completers ITT (LOCF)

PlaceboRimonabant

20 mg

PlaceboRimonabant

20 mg

-10

-8

-6

-4

-2

0

0 16 32 48 ITT LOCF

Wei

ght c

hang

e (k

g)

WeeksVan Gaal et al. The Lancet 2005; 365: 1389-97. Despres J-P, et al. N Engl J Med. 2005;353:2121-2134.

-1.5

-6.9-8.6

-2.3

-3.6

-8.6

-1.8

-6.6

37


Placebo

Rimonabant 20 mg Rimonabant 20 mg/PLB

RIO-NA: Weight Change over 2RIO-NA: Weight Change over 2--Years Years in Rein Re--randomized Patientsrandomized Patients

Weight (kg) Change from Baseline over 2 Years (Mean +/- SEM)

ITT (LOCF)

-7.4 kg ± 0.4

-2.3 kg ± 0.5

-3.2 kg ± 0.4

-10

-8

-6

-4

-2

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 LOCF-10

-8

-6

-4

-2

0

0 8 16 24 32 40 48 56 64 72 80 88 96 104 LOCF

Weeks

Wei

ght c

hang

e (K

g)

Pi-Sunyer FX et al. JAMA 2006;295:761-775.

38


RIO-NA: HDL-C and TG over 2 Years*RIO-NA: HDL-C and TG over 2 Years*

HDL-cholesterol Triglycerides

ITT, LOCF

Cha

nge

in T

rigly

cerid

es (%

)

Weeks

PlaceboRimonabant 20 mg Rimonabant 5 mg

-15

-10

-5

0

5

10

15

Weeks

Cha

nge

in H

DL-

chol

este

rol (

%)

0

5

10

15

20

25

30

+14.1%p<0.001

+8.4%ns

+7.8%

LOCF0 24 48 72 104

-1.9%p<0.001

+6.6%

+4.0%ns

LOCF0 24 48 72 104

*Patients on same treatment for 2 years


39


Chan

ge in

HDL

-C (%

)

30

25

20

15

10

5

00 12 24 36 52 Week

P<0.001

P=0.017

11.8

15.6

22.9

RIO-Lipids: Percent Change in HDL-C and TG Levels at 1 RIO-Lipids: Percent Change in HDL-C and TG Levels at 1 YearYear

Despres J-P, et al. N Engl J Med. 2005;353:2121-2134.

Rimonabant 20 mgRimonabant 5 mgPlacebo

Placebo: 11. 8%R5 mg : 14.2% (ns v. placebo) R20 mg : 19.1% (p< 0.001 v. placebo)

ITT, LOCF

Completers

Placebo: 0.0. %R5 mg : 1.2% R20 mg :-12.6% (p < 0.001 v. placebo)

10

5

0

-5

-10

-15

-200 12 24 36 52 Week

Chan

ge in

TG

(%)

P<0.001

+0.4

-3.6-3.6

-15.7

40


End Point

Placebo

Rimonabant 5 mg

Rimonabant 20 mg

P-value

PLB vs 20 mg

Weight loss (kg) - 1.4±0.2 - 2.3±0.2 - 5.3±0.3 <0.001

Decrease in waist circumference (cm)

- 1.9±0.3 - 2.9±0.3 - 5.2±0.3 <0.001

% of patients with weight loss ≥ 10%

2.0 6.2 16.4 <0.001

% of patients with weight loss ≥ 5%

14.5 21.7 49.4 <0.001

RIO-DIABETESRIO-DIABETESResults: Weight ChangesResults: Weight Changes

Scheen A. Late Breaking Clinical Trials. ADA Scientific Session 2005.


RIO-NA: Overall Safety Year 1

12.8 %9.4 %7.2 %Subjects discontinued due to adverse event

RimonabantPlacebo

4.5 %3.8 %3.5 %Subjects with any serious adverse event

85.5 %83.4 %82.0 %Subjects with any adverse event

44.9 %49.0 %49.1 %Overall discontinuations

20 mgn = 1219

5 mgn = 1214n = 607

Rimonabant


42


RIO-NA: Adverse Events LeadingRIO-NA: Adverse Events LeadingTo Drug Discontinuation in Year 1To Drug Discontinuation in Year 1

Placebo Rimonabant

(N=607)(%)

5 mg(N=1214)

(%)

20 mg(N=1219)

(%)

Psychiatric disorders 2.3 3.6 6.2 Depressed mood disorders 1.3 2.1 2.2 Anxiety 0.3 0.6 1.0 Irritability 0 0.2 0.5 Insomnia 0.2 <0.1 0.5Nervous system disorders 1.0 1.2 2.2 Headache 0.3 0.3 0.5 Dizziness 0.2 0 0.7Gastrointestinal disorders 0.7 0.7 1.6 Nausea 0.2 0.2 0.9

According to MedDRA, in any rimonabant groups : in main SOCs (>=1% ) and in at least 6 patients (0.5%).One patient may report several events


43


RIO-NA: Main Adverse Events Leading to Drug RIO-NA: Main Adverse Events Leading to Drug Discontinuation in Year 2*Discontinuation in Year 2*

2 (0.6)1 (0.3)0 (0) Anxiety4 (1.2)4 (1.3)3 (1.0) Depressed mood disorders

7 (2.1)6 (2.0)4 (1.3)Psychiatric disorders

20 mg(N=333)N (%)

5 mg(N=300)N (%)

(N=298)N (%)

RimonabantPlacebo

*Patients receiving the same treatment for 2 years


44


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 severe obesity


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 pyramid

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