Risks of Obesity and the Obesity EpidemicLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

Weight Management is Moving into the Workplace and Mainstream of Healthcare

bull Screening for Obesity in Adults The US Preventive Services Task Force recommends that clinicians screen all adult patients for obesity and offer intensive counseling and behavioral interventions to promote sustained weight loss for obese adults (Grade B recommendation)

bull Medicare now covers behavioral treatment of obesity

US Preventive Services Task Force Ann Intern Med 2003139930‐932

US Preventative Services Task Force

bull The USPSTF found that the most effective interventions were comprehensive and were of high intensity (12 to 26 sessions in a year)

bull Multiple behavioral management activities such as group sessions individual sessions setting weight-loss goals improving diet or nutrition physical activity sessions addressing barriers to change active use of self-monitoring and strategizing how to maintain lifestyle changes

bull A weight loss of 5 is considered clinically important by the US Food and Drug Administration (FDA)

httpwwwuspreventiveservicestaskforceorguspstf11obeseadultobesershtmAnn Intern Med 201226 June

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

Weight Management is Moving into the Workplace and Mainstream of Healthcare

bull Screening for Obesity in Adults The US Preventive Services Task Force recommends that clinicians screen all adult patients for obesity and offer intensive counseling and behavioral interventions to promote sustained weight loss for obese adults (Grade B recommendation)

bull Medicare now covers behavioral treatment of obesity

US Preventive Services Task Force Ann Intern Med 2003139930‐932

US Preventative Services Task Force

bull The USPSTF found that the most effective interventions were comprehensive and were of high intensity (12 to 26 sessions in a year)

bull Multiple behavioral management activities such as group sessions individual sessions setting weight-loss goals improving diet or nutrition physical activity sessions addressing barriers to change active use of self-monitoring and strategizing how to maintain lifestyle changes

bull A weight loss of 5 is considered clinically important by the US Food and Drug Administration (FDA)

httpwwwuspreventiveservicestaskforceorguspstf11obeseadultobesershtmAnn Intern Med 201226 June

Weight Management is Moving into the Workplace and Mainstream of Healthcare

bull Screening for Obesity in Adults The US Preventive Services Task Force recommends that clinicians screen all adult patients for obesity and offer intensive counseling and behavioral interventions to promote sustained weight loss for obese adults (Grade B recommendation)

bull Medicare now covers behavioral treatment of obesity

US Preventive Services Task Force Ann Intern Med 2003139930‐932

US Preventative Services Task Force

bull The USPSTF found that the most effective interventions were comprehensive and were of high intensity (12 to 26 sessions in a year)

bull Multiple behavioral management activities such as group sessions individual sessions setting weight-loss goals improving diet or nutrition physical activity sessions addressing barriers to change active use of self-monitoring and strategizing how to maintain lifestyle changes

bull A weight loss of 5 is considered clinically important by the US Food and Drug Administration (FDA)

httpwwwuspreventiveservicestaskforceorguspstf11obeseadultobesershtmAnn Intern Med 201226 June

US Preventative Services Task Force

bull The USPSTF found that the most effective interventions were comprehensive and were of high intensity (12 to 26 sessions in a year)

bull Multiple behavioral management activities such as group sessions individual sessions setting weight-loss goals improving diet or nutrition physical activity sessions addressing barriers to change active use of self-monitoring and strategizing how to maintain lifestyle changes

bull A weight loss of 5 is considered clinically important by the US Food and Drug Administration (FDA)

httpwwwuspreventiveservicestaskforceorguspstf11obeseadultobesershtmAnn Intern Med 201226 June

A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity

bull For obese Medicare beneficiaries whose counseling is furnished by a qualified primary care physician or other primary care practitioner and in a primary care setting the CMS proposes coverage of

bull One face-to-face visit every week for the first month bull One face-to-face visit every other week for months 2 to 6 and bull One face-to-face visit every month for months 7 to 12bull At the 6-month visit a reassessment of obesity and a

determination of the amount of weight loss should be performed To be eligible for face-to-face visits occurring once a month for an additional 6 months beneficiaries must have achieved a reduction in weight of at least 3 kg during the course of the first 6 months of intensive therapy

httpscmsgov (2011)

Sturm R Pub Hlth 2007 Jul121492-496

Biggest Increases in Clinically Severe Obesity US 1987‐2005

BMI gt30

BMI gt50larr

larr

larr

BMI gt40

7

Relationship Between BMI and Risk of Type 2 Diabetes

Chan J et al Diabetes Care 199417961Colditz G et al Ann Intern Med 1995122481

Age

-Adj

uste

d R

elat

ive

Ris

k

Body Mass Index (kgm2)

Women

Men

lt22 lt23 23ndash239

24ndash249

25ndash269

27ndash289

29ndash309

31ndash329

33ndash349

35+

102910

4310

5015

8122

158

44

276

403

540

932

67 116

213

421

100

75

50

25

0

Why Should I Treat Obesity

Medical Complications of Obesity Almost every organ system is affected

Phlebitisvenous stasis

Coronary heart disease

Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

Gout

Stroke

Diabetes

Osteoarthritis

Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

Dyslipidemia

Cataracts

Skin

Idiopathic intracranial hypertension

Severe pancreatitis

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Waist circumference

Blood pressure

Blood glucose

Triglycerides

HDL-cholesterol

LDL-cholesterol

Insulin resistance

Thrombotic risk

Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

NCEP ATP IIIdefinitionof themetabolicsyndrome

Antihypertensives

Oral antidiabetic agents

Antiplatelet agents

Lipid modifiers

Insulin sensitizers

Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

uarr insulin sensitivity darr hepatic glucose output

IL-6uarr

Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

TNFαuarr

Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

PAI-1uarr

Pro-atherogenicuarr atherothrombotic risk

IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

Risk FactorsPhenTPMMid

p-valuePhenTPMTop

p-value

CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

p-values represent comparisons to placebo

ITT-LOCF Placebo Comparisons

Gadde KM et al Lancet 2011377(9774)1341-52

Mid = 75 mg46 mgTop = 15 mg92 mg

In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

Diseasesbull ACCORD was stopped because of increased

mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

-34-48-48-88-59-29+73

Adams TD et al N Engl J Med 2007357(8)753-761

Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

Matched SubjectsSurgery Group (n=7925)

Co(n=

ntrol Group7925)

NoNo10000 person-yr No

No10000 person-yr

All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

Relationship Between BMI and Risk of Type 2 Diabetes

Chan J et al Diabetes Care 199417961Colditz G et al Ann Intern Med 1995122481

Age

-Adj

uste

d R

elat

ive

Ris

k

Body Mass Index (kgm2)

Women

Men

lt22 lt23 23ndash239

24ndash249

25ndash269

27ndash289

29ndash309

31ndash329

33ndash349

35+

102910

4310

5015

8122

158

44

276

403

540

932

67 116

213

421

100

75

50

25

0

Why Should I Treat Obesity

Medical Complications of Obesity Almost every organ system is affected

Phlebitisvenous stasis

Coronary heart disease

Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

Gout

Stroke

Diabetes

Osteoarthritis

Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

Dyslipidemia

Cataracts

Skin

Idiopathic intracranial hypertension

Severe pancreatitis

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Waist circumference

Blood pressure

Blood glucose

Triglycerides

HDL-cholesterol

LDL-cholesterol

Insulin resistance

Thrombotic risk

Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

NCEP ATP IIIdefinitionof themetabolicsyndrome

Antihypertensives

Oral antidiabetic agents

Antiplatelet agents

Lipid modifiers

Insulin sensitizers

Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

uarr insulin sensitivity darr hepatic glucose output

IL-6uarr

Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

TNFαuarr

Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

PAI-1uarr

Pro-atherogenicuarr atherothrombotic risk

IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

Risk FactorsPhenTPMMid

p-valuePhenTPMTop

p-value

CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

p-values represent comparisons to placebo

ITT-LOCF Placebo Comparisons

Gadde KM et al Lancet 2011377(9774)1341-52

Mid = 75 mg46 mgTop = 15 mg92 mg

In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

Diseasesbull ACCORD was stopped because of increased

mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

-34-48-48-88-59-29+73

Adams TD et al N Engl J Med 2007357(8)753-761

Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

Matched SubjectsSurgery Group (n=7925)

Co(n=

ntrol Group7925)

NoNo10000 person-yr No

No10000 person-yr

All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

Why Should I Treat Obesity

Medical Complications of Obesity Almost every organ system is affected

Phlebitisvenous stasis

Coronary heart disease

Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

Gout

Stroke

Diabetes

Osteoarthritis

Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

Dyslipidemia

Cataracts

Skin

Idiopathic intracranial hypertension

Severe pancreatitis

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Waist circumference

Blood pressure

Blood glucose

Triglycerides

HDL-cholesterol

LDL-cholesterol

Insulin resistance

Thrombotic risk

Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

NCEP ATP IIIdefinitionof themetabolicsyndrome

Antihypertensives

Oral antidiabetic agents

Antiplatelet agents

Lipid modifiers

Insulin sensitizers

Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

uarr insulin sensitivity darr hepatic glucose output

IL-6uarr

Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

TNFαuarr

Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

PAI-1uarr

Pro-atherogenicuarr atherothrombotic risk

IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

Risk FactorsPhenTPMMid

p-valuePhenTPMTop

p-value

CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

p-values represent comparisons to placebo

ITT-LOCF Placebo Comparisons

Gadde KM et al Lancet 2011377(9774)1341-52

Mid = 75 mg46 mgTop = 15 mg92 mg

In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

Diseasesbull ACCORD was stopped because of increased

mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

-34-48-48-88-59-29+73

Adams TD et al N Engl J Med 2007357(8)753-761

Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

Matched SubjectsSurgery Group (n=7925)

Co(n=

ntrol Group7925)

NoNo10000 person-yr No

No10000 person-yr

All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

Medical Complications of Obesity Almost every organ system is affected

Phlebitisvenous stasis

Coronary heart disease

Pulmonary diseaseasthmaobstructive sleep apneahypoventilation syndrome

Gall bladder diseaseReproductive abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

Gout

Stroke

Diabetes

Osteoarthritis

Cancerbreast uterus cervixcolon esophagus pancreaskidney prostate

Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis Hypertension

Dyslipidemia

Cataracts

Skin

Idiopathic intracranial hypertension

Severe pancreatitis

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Waist circumference

Blood pressure

Blood glucose

Triglycerides

HDL-cholesterol

LDL-cholesterol

Insulin resistance

Thrombotic risk

Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

NCEP ATP IIIdefinitionof themetabolicsyndrome

Antihypertensives

Oral antidiabetic agents

Antiplatelet agents

Lipid modifiers

Insulin sensitizers

Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

uarr insulin sensitivity darr hepatic glucose output

IL-6uarr

Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

TNFαuarr

Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

PAI-1uarr

Pro-atherogenicuarr atherothrombotic risk

IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

Risk FactorsPhenTPMMid

p-valuePhenTPMTop

p-value

CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

p-values represent comparisons to placebo

ITT-LOCF Placebo Comparisons

Gadde KM et al Lancet 2011377(9774)1341-52

Mid = 75 mg46 mgTop = 15 mg92 mg

In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

Diseasesbull ACCORD was stopped because of increased

mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

-34-48-48-88-59-29+73

Adams TD et al N Engl J Med 2007357(8)753-761

Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

Matched SubjectsSurgery Group (n=7925)

Co(n=

ntrol Group7925)

NoNo10000 person-yr No

No10000 person-yr

All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Waist circumference

Blood pressure

Blood glucose

Triglycerides

HDL-cholesterol

LDL-cholesterol

Insulin resistance

Thrombotic risk

Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

NCEP ATP IIIdefinitionof themetabolicsyndrome

Antihypertensives

Oral antidiabetic agents

Antiplatelet agents

Lipid modifiers

Insulin sensitizers

Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

uarr insulin sensitivity darr hepatic glucose output

IL-6uarr

Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

TNFαuarr

Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

PAI-1uarr

Pro-atherogenicuarr atherothrombotic risk

IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

Risk FactorsPhenTPMMid

p-valuePhenTPMTop

p-value

CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

p-values represent comparisons to placebo

ITT-LOCF Placebo Comparisons

Gadde KM et al Lancet 2011377(9774)1341-52

Mid = 75 mg46 mgTop = 15 mg92 mg

In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

Diseasesbull ACCORD was stopped because of increased

mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

-34-48-48-88-59-29+73

Adams TD et al N Engl J Med 2007357(8)753-761

Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

Matched SubjectsSurgery Group (n=7925)

Co(n=

ntrol Group7925)

NoNo10000 person-yr No

No10000 person-yr

All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

Waist circumference

Blood pressure

Blood glucose

Triglycerides

HDL-cholesterol

LDL-cholesterol

Insulin resistance

Thrombotic risk

Current Therapies Often Address Individual Risk Factors Cardiometabolic risk

NCEP ATP IIIdefinitionof themetabolicsyndrome

Antihypertensives

Oral antidiabetic agents

Antiplatelet agents

Lipid modifiers

Insulin sensitizers

Jupiter Trial Rosuvastatin reduced incidence of CV endpoints but increased HbA1cand reported cases of T2DM (plt01)

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

uarr insulin sensitivity darr hepatic glucose output

IL-6uarr

Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

TNFαuarr

Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

PAI-1uarr

Pro-atherogenicuarr atherothrombotic risk

IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

Risk FactorsPhenTPMMid

p-valuePhenTPMTop

p-value

CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

p-values represent comparisons to placebo

ITT-LOCF Placebo Comparisons

Gadde KM et al Lancet 2011377(9774)1341-52

Mid = 75 mg46 mgTop = 15 mg92 mg

In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

Diseasesbull ACCORD was stopped because of increased

mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

-34-48-48-88-59-29+73

Adams TD et al N Engl J Med 2007357(8)753-761

Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

Matched SubjectsSurgery Group (n=7925)

Co(n=

ntrol Group7925)

NoNo10000 person-yr No

No10000 person-yr

All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and

disease

Lactate Angiotensinogen

Leptin

Adipsin (Complement D)

TNF- α

FFAFat Stores

Lipoprotein Lipase

Plasminogen Activator Inhibitor 1

(PAI-1)

Resistin

Adiponectin

DM=diabetes mellitus FFA=free fatty acid PAI-1=plasminogen activator inhibitor-1 TNFα=tumor necrosis factor alpha IL-6=interleukin 6

Slide copy2007Louis J Aronne MD after Dr G Bray

Insulin

IL - 6

Estrogen

Hypertension

Thrombosis

Inflammation

Type 2 DM

DyslipidemiaType 2 DM

Arthritis

ASCVD

Asthma

C-C L2

Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

uarr insulin sensitivity darr hepatic glucose output

IL-6uarr

Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

TNFαuarr

Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

PAI-1uarr

Pro-atherogenicuarr atherothrombotic risk

IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

Risk FactorsPhenTPMMid

p-valuePhenTPMTop

p-value

CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

p-values represent comparisons to placebo

ITT-LOCF Placebo Comparisons

Gadde KM et al Lancet 2011377(9774)1341-52

Mid = 75 mg46 mgTop = 15 mg92 mg

In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

Diseasesbull ACCORD was stopped because of increased

mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

-34-48-48-88-59-29+73

Adams TD et al N Engl J Med 2007357(8)753-761

Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

Matched SubjectsSurgery Group (n=7925)

Co(n=

ntrol Group7925)

NoNo10000 person-yr No

No10000 person-yr

All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

Adiponectin Anti-atherogenicantidiabeticdarr darr foam cells darr vascular remodelling

uarr insulin sensitivity darr hepatic glucose output

IL-6uarr

Pro-atherogenicpro-diabeticuarr vascular inflammation darr insulin signalling

TNFαuarr

Pro-atherogenicpro-diabeticdarr insulin sensitivity in adipocytes (paracrine)

PAI-1uarr

Pro-atherogenicuarr atherothrombotic risk

IAA intra-abdominal adiposityMarette A Curr Opin Clin Nutr Metab Care 20025377-83

Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause

Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

Risk FactorsPhenTPMMid

p-valuePhenTPMTop

p-value

CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

p-values represent comparisons to placebo

ITT-LOCF Placebo Comparisons

Gadde KM et al Lancet 2011377(9774)1341-52

Mid = 75 mg46 mgTop = 15 mg92 mg

In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

Diseasesbull ACCORD was stopped because of increased

mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

-34-48-48-88-59-29+73

Adams TD et al N Engl J Med 2007357(8)753-761

Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

Matched SubjectsSurgery Group (n=7925)

Co(n=

ntrol Group7925)

NoNo10000 person-yr No

No10000 person-yr

All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

Risk FactorsPhenTPMMid

p-valuePhenTPMTop

p-value

CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

p-values represent comparisons to placebo

ITT-LOCF Placebo Comparisons

Gadde KM et al Lancet 2011377(9774)1341-52

Mid = 75 mg46 mgTop = 15 mg92 mg

In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

Diseasesbull ACCORD was stopped because of increased

mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

-34-48-48-88-59-29+73

Adams TD et al N Engl J Med 2007357(8)753-761

Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

Matched SubjectsSurgery Group (n=7925)

Co(n=

ntrol Group7925)

NoNo10000 person-yr No

No10000 person-yr

All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

In My Opinion The Winds of Change are Blowing in the Treatment of Chronic

Diseasesbull ACCORD was stopped because of increased

mortality in the tight control group 28 of whom gained gt 10kg compared to 14 in control^

bull Bariatric surgery trials show gt 80 reduction in diabetes mortality with weight loss

bull I believe we are in the midst of a shift from ldquoGlucocentricrdquo to ldquoWeight-Centricrdquo Management of T 2 DM

^ NEJM 3582545-2559 Adams TD et al N Engl J Med 2007357(8)753-761

-34-48-48-88-59-29+73

Adams TD et al N Engl J Med 2007357(8)753-761

Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

Matched SubjectsSurgery Group (n=7925)

Co(n=

ntrol Group7925)

NoNo10000 person-yr No

No10000 person-yr

All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

-34-48-48-88-59-29+73

Adams TD et al N Engl J Med 2007357(8)753-761

Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88

Matched SubjectsSurgery Group (n=7925)

Co(n=

ntrol Group7925)

NoNo10000 person-yr No

No10000 person-yr

All causes of death 213 376 321 571All deaths caused by disease 150 265 285 507Cardiovascular diseases 55 97 104 185Diabetes 2 04 19 34Cancer 31 55 73 133Other diseases 62 11 89 155All non-disease causes 63 111 36 64Accident unrelated to drugs 21 37 17 30Poisoning of undetermined intent 9 16 4 07Suicide 15 26 5 09Other nondisease cause 18 32 10 18

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

CC-18

Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period

$395

$230

$225

$150

$125

$0 $100 $200 $300 $400 $500

Obesity

Smoking

20 years aging

Problem drinking

Overweight

Sturm R Health Aff (Millwood) 2002 Mar-Apr21(2)245-53 Table Wall Street Journal 3132002

Obesity increased medication costs 77inpatient and outpatient costs 36

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

What-if scenarios (The Lancet forthcoming)

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

Redrawn from Hamman RF et al Diabetes Care 2006292102‐2107

Change in Weight from Baseline (kg)0‐10 ‐5 +5In

cide

nce Ra

te per 100

Person‐Years

10

20

15

5

0

How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later

n=530 overweight Chinese men and women with IGT mean BMI=26

17

0

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20Years of follow‐up

6‐year intervention hazard ratio = 049 (95 CI 033ndash073)20‐year follow‐up hazard ratio = 057 (95 CI 041ndash081)

Cumulative Incide

nce of Type 2 Diabe

tes ()

0

Lifestyle interventionControl

Treatment Follow‐up

Li et al Lancet 20083711783ndash9

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

Pharmacotherapy for Weight LossLouis J Aronne MD FACP

Professor of Clinical Medicine Weill Cornell Medical College

Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons

Director Comprehensive Weight Control Program

New York-Presbyterian HospitalWeill Cornell Medical Center New York NY

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

As faculty of Weill Cornell Medical College we are committed to providing transparency for any and all external relationships prior to giving an academic presentation

I am a consultant speaker advisor or receive research support fromBMS

Arena Aspire BariatricsMyos

GI Dynamics Novo NordiskOrexigenVivusZafgen

I may discuss off-label use of medications

Disclosure Page

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

uarrFood intakedarr energy expenditure

darrfood intake uarrenergy expenditure

Topiramate

Naltrexone

LorcaserinPramlintideGLP-1Leptin

BupropionPhentermine

New Compounds andCombination Interventions

c Louis J Aronne MDScience Feb 7 2003 Vol 299Illustration by Katharine Sutliff

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

Phentermine and TopiramateExtended-Release

bull Mechanism of actionndash Phentermine Sympathomimetic amine - releaserndash Topiramate Gabaergicglutamate modulation and carbonic

anhydrase inhibitionbull February 2012 FDA advisory committee votes 20-2 for

approval bull FDA approved July 2012

ndash Schedule IVndash Pregnancy Category X = REMS

Topiramate monotherapy exposure in pregnancy associated with 2- to 5-fold increased prevalence of oral clefts

bull 4 doses Titrate upbull Available only by mail orderbull Covered through Medco Express Scripts

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

Phentermine and TopiramateExtended-Release

bull Dose titrationndash Once dailyndash Start treatment with phentermine 375 mgtopiramate

23 mg extended-release daily for 14 daysndash After 14 days increase to the recommended dose of

phentermine 75 mgtopiramate 46 mg extended-release once daily

ndash May titrate upwards if needed to phen 15 top 92 mg strength

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507Discontinuation due to AEs 9 12 12 18Blurred vision 05 21 08 07Headache 07 17 02 09Insomnia 04 00 04 17Depression 02 00 08 14Tingling 00 04 10 12Irritability 01 08 08 12Anxiety 03 00 02 11Dizziness 02 04 12 08

Includes adverse events (AEs) by dose for EQUIP amp CONQUER which lead to discontinuation in gt 1 of patientsPress release Sept 9 2009 Available at httpirvivuscomreleasedetailcfmReleaseID=420114Accessed April 27 2010

PhenTPMMid

-104

Phentermine and Topiramate SEQUELWeight Loss Over Time

Garvey WT Ryan DH Look M Gadde KM Am J Clin Nutr 201295(2)297-308

Placebo-25

Plt00001 v placebo

Weight Loss

Week

Total Population

0

-2

-4

-6

-8

-10

-12

-14

-16

0 12 24 36 48 60 72 84 96 108

Weight Loss ITT-LOCF

PhenTPMTop

-114

Mid = 75 mg46 mgTop = 15 mg92 mg

CONQUER Significant Improvement in Cardiovascular Risk Factors

(LS Mean Wt Loss)

QNEXAMid(78)

P valueQNEXATop

(98) P value

Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

Diastolic BP (mmHg) ‐07 NS ‐11 00031

Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

LDL ( ∆) 04 NS ‐28 00069

HDL ( ∆) 40 lt00001 56 lt00001

P values represent comparisons to placebo NS= non‐significant

ITT‐LOCF Placebo ComparisonsTotal Study Population

Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

CONQUER Significant Improvement in Cardiovascular Risk Factors

(LS Mean Wt Loss)

QNEXAMid(78)

P valueQNEXATop

(98) P value

Waist Circumference (cm) ‐52 lt00001 ‐68 lt00001

Systolic BP (mmHg) ‐23 00008 ‐32 lt00001

Diastolic BP (mmHg) ‐07 NS ‐11 00031

Triglycerides ( ∆) ‐133 lt00001 ‐153 lt00001

Total Cholesterol ( ∆) ‐16 00345 ‐30 lt00001

LDL ( ∆) 04 NS ‐28 00069

HDL ( ∆) 40 lt00001 56 lt00001

P values represent comparisons to placebo NS= non‐significant

ITT‐LOCF Placebo ComparisonsTotal Study Population

Davidson MH et al Am J Cardiol 2013 Jan 29 pii S0002‐9149(12)02641‐0 doi 101016jamjcard201212038

Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors

Risk FactorsPhenTPMMid

p-valuePhenTPMTop

p-value

CRP lt0001 lt0001Fibrinogen lt005 lt005Adiponectin lt00001 lt00001

p-values represent comparisons to placebo

ITT-LOCF Placebo Comparisons

Gadde KM et al Lancet 2011377(9774)1341-52

Mid = 75 mg46 mgTop = 15 mg92 mg

Lorcaserin

bull Selective 5‐HT2C receptor agonist designed to promote weight loss

bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

bull Dose - 10 mg BIDbull Most common side effects headache nausea

dizziness dry mouth

BLOOM Study Body Weight Over Years 1 and 2

Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

Bod

y W

eigh

t (kg

)

102

100

98

96

94

92

90

0

Year 1

Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

Year 2

Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

minus090plusmn033287plusmn056005plusmn033

057plusmn034403plusmn058minus021plusmn034

001

049

72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

minus20plusmn03minus092plusmn023minus11plusmn01

minus16plusmn04 minus023plusmn023 minus09plusmn01

0499014026

BLOOM StudyKey Secondary Endpoints

Smith SR et al N Engl J Med 2010363245-256

BLOOM-DMChange in Glycemic Parameters

P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

00

-05

-10

-150 12 24 36 52

Cha

nge

from

bas

elin

e (

)

A1c

Study week

0

-10

-20

-30

-400 12 24 52

Cha

nge

from

bas

elin

e m

gdl

)

Fasting plasma glucose

Study week

Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

55

N () Lorcaserin(N = 1593)

Placebo(N = 1584)

Headache 287 (180) 175 (110)

Dizziness 130 (82) 60 (38)

Nausea 119 (75) 85 (54)

Constipation 106 (67) 64 (40)

Fatigue 95 (60) 48 (30)

Dry mouth 83 (52) 37 (23)

Smith SR et al ADA 2009 Late‐Breaking Abstract 96

LorcaserinNo Increase in Rate of Valvulopathy

Smith SR et al N Engl J Med 2010363245-256

10

8

6

4

2

024 52 76 104

1351714

9

19

3421Patie

nts

()

Week

Lorcaserin in yr 1 and 2

Lorcaserin in yr 1 Placebo in yr 2

Placebo in yr 1 and 2

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Obesity Treatments in Late Development

Kushner RF Expert Opin Pharmacother 200891339-1350

Agents ActionBupropionNaltrexone

bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

Liraglutide bull GLP-1 agonist

BupropionNaltrexone

bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

bull BupropionNaltrexone will have first completed CV outcome study

Buproprion ndash Naltrexone

Greenway FL et al Lancet 2010376(9741)595-605

0

-2

-4

-6

-8

-100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Wei

ght c

hang

e fro

m b

asel

ine

()

Placebo

Naltrexone 16 mg plus bupropion

Naltrexone 32 mg plus bupropion

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

Lorcaserin

bull Selective 5‐HT2C receptor agonist designed to promote weight loss

bull Schedule IV ndash Expected soonbull Indication weight loss and maintenance of

weight loss in patients with BMI gt30 kgm2 or BMI gt27 kgm2 + weight-related comorbidcondition(s)

bull Dose - 10 mg BIDbull Most common side effects headache nausea

dizziness dry mouth

BLOOM Study Body Weight Over Years 1 and 2

Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

Bod

y W

eigh

t (kg

)

102

100

98

96

94

92

90

0

Year 1

Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

Year 2

Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

minus090plusmn033287plusmn056005plusmn033

057plusmn034403plusmn058minus021plusmn034

001

049

72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

minus20plusmn03minus092plusmn023minus11plusmn01

minus16plusmn04 minus023plusmn023 minus09plusmn01

0499014026

BLOOM StudyKey Secondary Endpoints

Smith SR et al N Engl J Med 2010363245-256

BLOOM-DMChange in Glycemic Parameters

P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

00

-05

-10

-150 12 24 36 52

Cha

nge

from

bas

elin

e (

)

A1c

Study week

0

-10

-20

-30

-400 12 24 52

Cha

nge

from

bas

elin

e m

gdl

)

Fasting plasma glucose

Study week

Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

55

N () Lorcaserin(N = 1593)

Placebo(N = 1584)

Headache 287 (180) 175 (110)

Dizziness 130 (82) 60 (38)

Nausea 119 (75) 85 (54)

Constipation 106 (67) 64 (40)

Fatigue 95 (60) 48 (30)

Dry mouth 83 (52) 37 (23)

Smith SR et al ADA 2009 Late‐Breaking Abstract 96

LorcaserinNo Increase in Rate of Valvulopathy

Smith SR et al N Engl J Med 2010363245-256

10

8

6

4

2

024 52 76 104

1351714

9

19

3421Patie

nts

()

Week

Lorcaserin in yr 1 and 2

Lorcaserin in yr 1 Placebo in yr 2

Placebo in yr 1 and 2

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Obesity Treatments in Late Development

Kushner RF Expert Opin Pharmacother 200891339-1350

Agents ActionBupropionNaltrexone

bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

Liraglutide bull GLP-1 agonist

BupropionNaltrexone

bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

bull BupropionNaltrexone will have first completed CV outcome study

Buproprion ndash Naltrexone

Greenway FL et al Lancet 2010376(9741)595-605

0

-2

-4

-6

-8

-100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Wei

ght c

hang

e fro

m b

asel

ine

()

Placebo

Naltrexone 16 mg plus bupropion

Naltrexone 32 mg plus bupropion

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

BLOOM Study Body Weight Over Years 1 and 2

Smith SR et al N Engl J Med 2010363245-256 Study Week0 8 16 24 32 40 48 56 64 72 80 88 96 104

Bod

y W

eigh

t (kg

)

102

100

98

96

94

92

90

0

Year 1

Placebo in year 1 and 2 (n = 684)Lorcaserin in year 1 placebo in year 2 (n = 275)Lorcaserin in year 1 and 2 (n = 564)

Year 2

Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

minus090plusmn033287plusmn056005plusmn033

057plusmn034403plusmn058minus021plusmn034

001

049

72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

minus20plusmn03minus092plusmn023minus11plusmn01

minus16plusmn04 minus023plusmn023 minus09plusmn01

0499014026

BLOOM StudyKey Secondary Endpoints

Smith SR et al N Engl J Med 2010363245-256

BLOOM-DMChange in Glycemic Parameters

P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

00

-05

-10

-150 12 24 36 52

Cha

nge

from

bas

elin

e (

)

A1c

Study week

0

-10

-20

-30

-400 12 24 52

Cha

nge

from

bas

elin

e m

gdl

)

Fasting plasma glucose

Study week

Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

55

N () Lorcaserin(N = 1593)

Placebo(N = 1584)

Headache 287 (180) 175 (110)

Dizziness 130 (82) 60 (38)

Nausea 119 (75) 85 (54)

Constipation 106 (67) 64 (40)

Fatigue 95 (60) 48 (30)

Dry mouth 83 (52) 37 (23)

Smith SR et al ADA 2009 Late‐Breaking Abstract 96

LorcaserinNo Increase in Rate of Valvulopathy

Smith SR et al N Engl J Med 2010363245-256

10

8

6

4

2

024 52 76 104

1351714

9

19

3421Patie

nts

()

Week

Lorcaserin in yr 1 and 2

Lorcaserin in yr 1 Placebo in yr 2

Placebo in yr 1 and 2

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Obesity Treatments in Late Development

Kushner RF Expert Opin Pharmacother 200891339-1350

Agents ActionBupropionNaltrexone

bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

Liraglutide bull GLP-1 agonist

BupropionNaltrexone

bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

bull BupropionNaltrexone will have first completed CV outcome study

Buproprion ndash Naltrexone

Greenway FL et al Lancet 2010376(9741)595-605

0

-2

-4

-6

-8

-100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Wei

ght c

hang

e fro

m b

asel

ine

()

Placebo

Naltrexone 16 mg plus bupropion

Naltrexone 32 mg plus bupropion

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

Endpoint Lorcaserin Placebo P valueWaist circumference (cm) minus68plusmn02 minus39plusmn02 lt001BMI (kgm2) minus209plusmn006 minus078plusmn005 lt001SBPDBP (mm Hg) minus14plusmn03minus11plusmn02 minus08plusmn03minus06plusmn02 0401Cholesterol ( ∆)Total LDLHDL

minus090plusmn033287plusmn056005plusmn033

057plusmn034403plusmn058minus021plusmn034

001

049

72Triglycerides minus615plusmn103 minus014plusmn099 lt001SafetyHR (beatsmin)PASP (mm Hg)Beck depression II score

minus20plusmn03minus092plusmn023minus11plusmn01

minus16plusmn04 minus023plusmn023 minus09plusmn01

0499014026

BLOOM StudyKey Secondary Endpoints

Smith SR et al N Engl J Med 2010363245-256

BLOOM-DMChange in Glycemic Parameters

P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

00

-05

-10

-150 12 24 36 52

Cha

nge

from

bas

elin

e (

)

A1c

Study week

0

-10

-20

-30

-400 12 24 52

Cha

nge

from

bas

elin

e m

gdl

)

Fasting plasma glucose

Study week

Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

55

N () Lorcaserin(N = 1593)

Placebo(N = 1584)

Headache 287 (180) 175 (110)

Dizziness 130 (82) 60 (38)

Nausea 119 (75) 85 (54)

Constipation 106 (67) 64 (40)

Fatigue 95 (60) 48 (30)

Dry mouth 83 (52) 37 (23)

Smith SR et al ADA 2009 Late‐Breaking Abstract 96

LorcaserinNo Increase in Rate of Valvulopathy

Smith SR et al N Engl J Med 2010363245-256

10

8

6

4

2

024 52 76 104

1351714

9

19

3421Patie

nts

()

Week

Lorcaserin in yr 1 and 2

Lorcaserin in yr 1 Placebo in yr 2

Placebo in yr 1 and 2

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Obesity Treatments in Late Development

Kushner RF Expert Opin Pharmacother 200891339-1350

Agents ActionBupropionNaltrexone

bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

Liraglutide bull GLP-1 agonist

BupropionNaltrexone

bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

bull BupropionNaltrexone will have first completed CV outcome study

Buproprion ndash Naltrexone

Greenway FL et al Lancet 2010376(9741)595-605

0

-2

-4

-6

-8

-100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Wei

ght c

hang

e fro

m b

asel

ine

()

Placebo

Naltrexone 16 mg plus bupropion

Naltrexone 32 mg plus bupropion

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

BLOOM-DMChange in Glycemic Parameters

P lt001 P lt05 LS mean change plusmn SEMOrsquoNeil PM et al Obesity 201220(7)1426-36 httpwwwnaturecomdoifinder101038oby201266

00

-05

-10

-150 12 24 36 52

Cha

nge

from

bas

elin

e (

)

A1c

Study week

0

-10

-20

-30

-400 12 24 52

Cha

nge

from

bas

elin

e m

gdl

)

Fasting plasma glucose

Study week

Lorcaserin 10 mg BID Lorcaserin 10 mg Placebo

Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

55

N () Lorcaserin(N = 1593)

Placebo(N = 1584)

Headache 287 (180) 175 (110)

Dizziness 130 (82) 60 (38)

Nausea 119 (75) 85 (54)

Constipation 106 (67) 64 (40)

Fatigue 95 (60) 48 (30)

Dry mouth 83 (52) 37 (23)

Smith SR et al ADA 2009 Late‐Breaking Abstract 96

LorcaserinNo Increase in Rate of Valvulopathy

Smith SR et al N Engl J Med 2010363245-256

10

8

6

4

2

024 52 76 104

1351714

9

19

3421Patie

nts

()

Week

Lorcaserin in yr 1 and 2

Lorcaserin in yr 1 Placebo in yr 2

Placebo in yr 1 and 2

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Obesity Treatments in Late Development

Kushner RF Expert Opin Pharmacother 200891339-1350

Agents ActionBupropionNaltrexone

bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

Liraglutide bull GLP-1 agonist

BupropionNaltrexone

bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

bull BupropionNaltrexone will have first completed CV outcome study

Buproprion ndash Naltrexone

Greenway FL et al Lancet 2010376(9741)595-605

0

-2

-4

-6

-8

-100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Wei

ght c

hang

e fro

m b

asel

ine

()

Placebo

Naltrexone 16 mg plus bupropion

Naltrexone 32 mg plus bupropion

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1

55

N () Lorcaserin(N = 1593)

Placebo(N = 1584)

Headache 287 (180) 175 (110)

Dizziness 130 (82) 60 (38)

Nausea 119 (75) 85 (54)

Constipation 106 (67) 64 (40)

Fatigue 95 (60) 48 (30)

Dry mouth 83 (52) 37 (23)

Smith SR et al ADA 2009 Late‐Breaking Abstract 96

LorcaserinNo Increase in Rate of Valvulopathy

Smith SR et al N Engl J Med 2010363245-256

10

8

6

4

2

024 52 76 104

1351714

9

19

3421Patie

nts

()

Week

Lorcaserin in yr 1 and 2

Lorcaserin in yr 1 Placebo in yr 2

Placebo in yr 1 and 2

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Obesity Treatments in Late Development

Kushner RF Expert Opin Pharmacother 200891339-1350

Agents ActionBupropionNaltrexone

bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

Liraglutide bull GLP-1 agonist

BupropionNaltrexone

bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

bull BupropionNaltrexone will have first completed CV outcome study

Buproprion ndash Naltrexone

Greenway FL et al Lancet 2010376(9741)595-605

0

-2

-4

-6

-8

-100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Wei

ght c

hang

e fro

m b

asel

ine

()

Placebo

Naltrexone 16 mg plus bupropion

Naltrexone 32 mg plus bupropion

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

LorcaserinNo Increase in Rate of Valvulopathy

Smith SR et al N Engl J Med 2010363245-256

10

8

6

4

2

024 52 76 104

1351714

9

19

3421Patie

nts

()

Week

Lorcaserin in yr 1 and 2

Lorcaserin in yr 1 Placebo in yr 2

Placebo in yr 1 and 2

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Obesity Treatments in Late Development

Kushner RF Expert Opin Pharmacother 200891339-1350

Agents ActionBupropionNaltrexone

bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

Liraglutide bull GLP-1 agonist

BupropionNaltrexone

bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

bull BupropionNaltrexone will have first completed CV outcome study

Buproprion ndash Naltrexone

Greenway FL et al Lancet 2010376(9741)595-605

0

-2

-4

-6

-8

-100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Wei

ght c

hang

e fro

m b

asel

ine

()

Placebo

Naltrexone 16 mg plus bupropion

Naltrexone 32 mg plus bupropion

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Obesity Treatments in Late Development

Kushner RF Expert Opin Pharmacother 200891339-1350

Agents ActionBupropionNaltrexone

bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

Liraglutide bull GLP-1 agonist

BupropionNaltrexone

bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

bull BupropionNaltrexone will have first completed CV outcome study

Buproprion ndash Naltrexone

Greenway FL et al Lancet 2010376(9741)595-605

0

-2

-4

-6

-8

-100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Wei

ght c

hang

e fro

m b

asel

ine

()

Placebo

Naltrexone 16 mg plus bupropion

Naltrexone 32 mg plus bupropion

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

Obesity Treatments in Late Development

Kushner RF Expert Opin Pharmacother 200891339-1350

Agents ActionBupropionNaltrexone

bull Dopaminenoradrenaline reuptake inhibitorbull Opioid receptor antagonist

Liraglutide bull GLP-1 agonist

BupropionNaltrexone

bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

bull BupropionNaltrexone will have first completed CV outcome study

Buproprion ndash Naltrexone

Greenway FL et al Lancet 2010376(9741)595-605

0

-2

-4

-6

-8

-100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Wei

ght c

hang

e fro

m b

asel

ine

()

Placebo

Naltrexone 16 mg plus bupropion

Naltrexone 32 mg plus bupropion

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

BupropionNaltrexone

bull Mechanism of Actionndash Bupropion - Dopaminenoradrenaline reuptake inhibitorndash Naltrexone- Opioid receptor antagonist

bull Was approved by FDA committee but FDA did not approve until a CV outcome study is performed 2nd concerns about BP and P in some patients

bull The Light Study is now underway and reported to be enrolling well under PI Dr Nissen

bull BupropionNaltrexone will have first completed CV outcome study

Buproprion ndash Naltrexone

Greenway FL et al Lancet 2010376(9741)595-605

0

-2

-4

-6

-8

-100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Wei

ght c

hang

e fro

m b

asel

ine

()

Placebo

Naltrexone 16 mg plus bupropion

Naltrexone 32 mg plus bupropion

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

Buproprion ndash Naltrexone

Greenway FL et al Lancet 2010376(9741)595-605

0

-2

-4

-6

-8

-100 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Weeks

Wei

ght c

hang

e fro

m b

asel

ine

()

Placebo

Naltrexone 16 mg plus bupropion

Naltrexone 32 mg plus bupropion

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

Liraglutide for Weight Loss in Patients with Type 2 Diabetes

bull GLP-1 analog approved for treatment of type 2 diabetes

bull Anorectic effect mediated both by the activation of GLP-1 receptor expressed on vagal afferents and by the GLP-1R activation in CNS

bull Affects visceral fat adiposity appetite food preference and cardiovascular biomarkers in patients with type 2 diabetes

Inoue K et al Cardiovasc Diabetol 2011 10109 doi1011861475-2840-10-109

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

Liraglutide Weight Loss Over 2 Years ITT Observed Means

Astrup A et al Int J Obes (Lond) 201236(6)843-54

FromScreening

-94 kg

-67 kg-88 kg

-99 kg-94 kg

-103 kg

ITT intention to treat

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

Phase III Study Outcomes Compared

Buproprion SR (360 mgd) Naltrexone SR (32 mgd)

Lorcaserin(20 mgd)

Phentermine Topiramate CR

COR1 COR-I2 COR-II3 NB3043 BLOOM4 BLOSSOM5 EQUIP CONQUER

Number of patients (ITT-LOCF)

793 obese 1453 obese

1281 obese

502 type II diabetes

3182 obese 4008 obese

1230 obese BMI 44

2448 comorbidBMI 36

Mean change compared with placebo from base

93 vs5 1c

61a vs13c

64a vs12

50 a vs12c

58 vs22c

48 vs28c

11 Fullbvs 16

104 Fullb 84 Midb

vs 18

51 Lowb vs16c

Categorical change 5 compared with placebo from base

56 vs43

48a vs164

563a

vs 171445a vs189

475b

vs 203472b vs25

67 Fullb 45 Lowb vs17

70 Fullb 62 Midb

vs 21

Phenterminetopiramate doses Low 375 mg phentermine23 mg topiramate Mid 75 mg phentermine 46 mg topiramate Full 15 mg phentermine 92 mg topiramateITT-LOCF intent-to-treat last observation carried forwardData not available aP lt 001 vs placebo bP lt 0001 vs placebo

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

Treatment Gap in theManagement of Obesity

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

What will fill the gap

Too risky for many peopleNot effective enoughfor many people

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity

Treatment Gap in theManagement of Obesity

0 5 10 15 20 25 30 35

Diet and Lifestyle Lap Band Gastric Bypass

TreatmentGap

Too risky for many peopleNot effective enoughfor many people Pharmacotherapy

Less invasive procedures

Physicians Need Effective Pharmacotherapies That Will Reduce Weight Significantly and Reduce Weight-related Comorbidities

What will fill the gap

• Slide Number 1
• Slide Number 2
• Weight Management is Moving into the Workplace and Mainstream of Healthcare
• US Preventative Services Task Force
• A Proposal from CMS about Coverage for Intensive Behavioral Therapy for Obesity
• Slide Number 6
• Biggest Increases in Clinically Severe Obesity US 1987-2005
• Relationship Between BMI and Risk of Type 2 Diabetes
• Slide Number 9
• Medical Complications of Obesity Almost every organ system is affected
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Current Therapies Often Address Individual Risk Factors Cardiometabolic risk
• Excess adipose tissue leads to increased expression of some hormones suppression of others leading to inflammation and disease
• Are You Treating These Drivers of Cardiometabolic Risk Should You Treat The Underlying Cause
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• In My Opinion The Winds of Change are Blowing in the Treatment of Chronic Diseases
• Bariatric Surgery Reduces Overall Mortality Diabetes Mortality by 88
• Health Care Costs Attributable to ObesityEstimates of what various conditions add to health-care service costs over a 12-month period
• What-if scenarios (The Lancet forthcoming)
• How Much Weight Loss Is Needed to Prevent T2DMndashNot Very Much The DPP Experience
• In the Da Qing Study 6-year Intervention Led to Lower Incidence of Type 2 Diabetes 14 Years Later
• Slide Number 22
• Slide Number 23
• New Compounds andCombination Interventions
• Phentermine and Topiramate Extended-Release
• Phentermine and Topiramate Extended-Release
• EQUIP amp CONQUER Discontinuation RateDue to AEs in All Doses Studied
• Phentermine and Topiramate SEQUELWeight Loss Over Time
• CONQUER Significant Improvement in Cardiovascular Risk Factors
• Phentermine and Topiramate Extended Release CONQUER ndash Inflammatory Risk Factors
• Lorcaserin
• BLOOM Study Body Weight Over Years 1 and 2
• BLOOM StudyKey Secondary Endpoints
• BLOOM-DMChange in Glycemic Parameters
• Lorcaserin Adverse Events Reported by 5 or More in Any Group in Year 1
• LorcaserinNo Increase in Rate of Valvulopathy
• Phase III Study Outcomes Compared
• Obesity Treatments in Late Development
• BupropionNaltrexone
• Buproprion ndash Naltrexone
• Liraglutide for Weight Loss in Patients with Type 2 Diabetes
• Liraglutide Weight Loss Over 2 Years ITT Observed Means
• Phase III Study Outcomes Compared
• Treatment Gap in theManagement of Obesity
• Treatment Gap in theManagement of Obesity