20120328 29 emdac b1 03 guest coreslides

7/28/2019 20120328 29 EMDAC B1 03 Guest CoreSlides

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Pathophysiology of Obesity

and CVD

Endocrine and Metabolism Drug AdvisoryCommittee

Food and Drug Administration

March 28, 2012

Robert H. Eckel, M.D.Professor of Medicine

Professor of Physiology and Biophysics

Charles A. Boettcher II Chair in AtherosclerosisUniversity of Colorado Anschutz Medical Campus


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CVD Mortality and Obesity:

Cancer Prevention Study II

0.6

1.0

1.4

1.8

2.2

2.6

3.0 Men (n=84,376)Women (n=217,857)


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Metabolic Pathophysiology

of Obesity and CVD

Hypertension

Dyslipidemia

Inflammation Diabetes

3


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4


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The Role of Adipose Tissue

and Adipose Tissue

Distribution andthe Metabolic Syndrome

5


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Visceral vs. Subcutaneous Adipose

TissueAdipose Tissue

Function

Visceral vs.

SubcutaneousInsulin action Subcutaneous

Catecholamine action Visceral

Leptin Subcutaneous

PAI-1 Visceral/Subcutaneous

Angiotensinogen Visceral

IL-6 (cytokines) Visceral

Adiponectin Subcutaneous

6


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Subcutaneous Fat

Abdominal Muscle

Layer

Intra-abdominal

Fat

Visceral Adiposity:

The Critical Adipose Depot

7


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77

4655

106

8997

128

110

83

Abdominal Obesity and Coronary Heart

Disease in Women: The Nurses Health Study

LowMiddleHigh

High (81.8 -


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Relationship Between Visceral Adipose

Tissue and Insulin Action1818

1616

1414

1212

1010

88

66

44

22

0000 1,0001,000 2,0002,000 3,0003,000 4,0004,000 5,0005,000

Visceral adipose tissue volumeVisceral adipose tissue volumeper unit surface area (mL/mper unit surface area (mL/m22))

Glucosedisposal(mg/kgLBM/min)

Glucosedisposal(mg/kgLBM/min)

Banerji et al.Am J Physiol1997; 273: E425E432

WomenWomen

MenMen

9


10/186Weyer C et al. J Clin Invest104: 787, 1999

500

400

300

200

100

00 1 2 3 4 5

InsulinSecretion(U/mL

)

Insulin Action (mg/kg EMBS per minute)

Normal Glucose

Tolerance

InsulinResistance

-CellFailure

ImpairedGlucose

Tolerance

Type 2

Diabetes

Pathogenesis: -Cell Compensation

and Decompensation and T2DM

10


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Hypertension

FFA

FFA

Glycogen

Triglyceride(intramuscular droplet)

CO2

-

-

-

Glucose

{ ITNF-L-6{

PAI-1Fibrinogen

ProthromboticState

Adiponectin-

IL-6

Insulin

InsulinVLDL

TG

C-III

C-II

B-100HDL cholesterol

small dense LDLand

-

CRP

SNSFFA

Eckel RH et al, Lancet365:1415, 2005

Insulin Resistance Metabolism

11


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The Link Between Insulin Resistance

and Endothelial Dysfunction

Steinberg HO, Baron AD. Diabetologia. 2002;45:623-634.

Caballero AE. Obesity Res. 2003;11:1278-1289.

Lipolytically Active

Abdominal Adipose

Tissue IL-1, IL-6, TNF

Vasodilation

Shear Stress

Inflammation

AtherosclerosisThrombosis

CRP

PAI-1

Vascular Endothelium

12


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Pathogenesis of Hypertriglyceridemia

inThe Metabolic Syndrome

production of atherogenic apoB-containing TG-rich lipoproteins Small VLDL (Sf 20-60)

Apo B:C-III:E-containing VLDL

IDL (Sf 10-20)

Remnants

removal of TG-rich lipoproteins

13


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FFA

VLDL

Insulin

Resistance

TGSynthesis

apo B-100apo C-III

SREBP-1c

TG Storage

VLDL

apo C-III

LPL

Hypertriglyceridemia

Obesity

TG

FFA

Fat Mass

Eckel RH,ATVB, 31:1946, 2011


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Pathogenesis of Decreased HDL

Cholesterol inThe Metabolic Syndrome

cholesterol content of HDL TG CETP LPL production of HDL2

HDL3 clearance

15


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Inflammatory Markers and Insulin

Resistance

Yudkin, JS et al,ATVB 19:976, 200115


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CRP by Number of Metabolic Disorders

(Dyslipidemia, Upper Body Adiposity,

Insulin Resistance, Hypertension)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Mea

nValueofLogCRP

0 1 2 3 4

Number of Metabolic Disorders

Festa et al. Circulation 102:42-7, 200016


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More Metabolic Syndrome

Other associated conditions

uric acid and gout Cognitive dysfunction Polycystic ovarian syndrome

Non-alcoholic fatty liver disease

Obstructive sleep apnea

17


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19


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Cardiac Abnormalities in Obesity

Coronary heart disease Diastolic dysfunction

Left ventricular hypertrophy +/- failure eccentric concentric

adipositas cordis (cardiomyopathy of obesity) Right ventricular hypertrophy

Pulmonary hypertension

obstructive sleep apnea

central hypoventilation

thromboembolic disease

deep venous thrombosis

Autonomic dysfunction Arrhythmias, prolonged QTc, sudden death

20


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21

20


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Cardiovascular Adaptations

in Obesity

Interstitial fluid

Vasodilatation

peripheral resistance

Left ventricular end diastolic

pressure

Heart rate

Cardiac outputPoirier P and Eckel RH: The Heart and Obesity, Chpt 83, 2000, In: Hurst's The Heart22


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Coronary heart disease

23

H d R ti f th Ri k f Di b t


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Hazard Ratio for the Risk ofDiabetesOver 17 Years in Healthy Young Adults, According

to BMI in Adolescence and in Adulthood37,674 young men, Staff Periodic Exam,

Israeli Army Medical Corps

24 Tirosh A et al. NEJM364:1315, 2011

H d R ti f th Ri k f C H t Di


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Hazard Ratio for the Risk ofCoronary Heart DiseaseOver 17 Years in Healthy Young Adults, According

to BMI in Adolescence and in Adulthood37,674 young men, Staff Periodic Exam,

Israeli Army Medical Corps

25 Tirosh A et al. NEJM364:1315, 2011


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adipositas cordis (cardiomyopathy of obesity) Right ventricular hypertrophy

Pulmonary hypertension




Deep venous thrombosis

26


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Myocardial Response to ObesIty

and Insulin Resistance Cardiac myocyte hypertrophy

Insulin-like growth factor-1

Myocardial ischemia

Microangiopathy

Endothelial dysfunction

Reduced cardiac function

Impairment in myocyte calcium

transport

Alteration in contractile proteins

Interstitial fibrosis

Cardiac arrhythmias

Prolonged action potential

Electrical remodeling

Autonomic neuropathy

Parasympathetic Sympathetic

Metabolic factors

Dysglycemia

Intracellular triglyceride

accumulation

Myocardial

inflammation Oxidative stress

AGEs

Mitochondrial dysfunction Apoptosis

27

H t i d Ob it


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Hypertension and Obesity:

NHANES III (1988-1994)

Brown CD et al, Obes Res 8:605, 2000


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Mechanisms Relating Obesity to

Hypertension

Narkiewicz K et al Obes Rev7:155, 2006


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Duration of Severe Obesity:

Systolic Blood Pressure

Alpert MA et al. Am J Card 76:1194, 1995

110

115

120

125

130

135

140

0 5 10 15 20 25 30

years

Systolic

bloodpres

sure(mmH

G)

30


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Duration of Severe Obesity:

LV End Diastolic Dimension

Alpert MA et al. Am J Card 76:1194, 1995

4

4.5

5

5.5

6

6.5

7

0 5 10 15 20 25 30

years

LV

dim

ens

ion

dia

stole

(mm

)

31

CVD M li H i i h


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CVD Mortality, Hypertension in the

Womens Health Initiative

Oparil S, Card Rev14:267, 200632

C t ib t t H t i i th


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Contributors to Hypertension in the

Womens Health Initiative

Oparil S, Card Rev14:267, 200633

C di Ab li i i Ob i


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adipositas cordis (cardiomyopathy of obesity)

Right ventricular hypertrophy Pulmonary hypertension




Deep venous thrombosis

Autonomic dysfunction Arrhythmias, prolonged QTc, sudden death34


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ECG Changes Found in Obesity

Clinically significant

Heart rate

QRS interval

QT

c

interval

False positive criteria for inferior myocardial infarction

Less clinically significant

QT dispersion

SAECG (late potentials)

or

QRS voltage

PR interval

ST-T abnormalities

ST depression

Left axis deviation

Flattening of the T wave (inferolateral leads)

Left atrial abnormalities

Poirier P and Eckel RH: Cardiovascular Complications of Obesity and the

Metabolic Syndrome, In: Cardiovascular Medicine, 200735


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Arrhythmias in Obesity

Atrial fibrillation

Late potentials (SAECG) Prevalence and number of abnormalities increases with

increasing obesity Irrespective of the presence of hypertension or

diabetes

May be facilitated by Myocyte hypertrophy

Abnormal heart rate variability

Focal myocardial disarray Fibrosis

Fat infiltration

Mononuclear infiltration

Poirier P, Cardiovascular complications of obesity and weight loss :

pathogenesis and clinical recognition, Monograph, 200636

B fit f W i ht R d ti th


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Benefits of Weight Reduction on the

Cardiovascular System

blood volume

stroke volume

cardiac output pulmonary capillary wedge pressure

left ventricular mass

Improvement of left ventricular diastolic dysfunction Improvement of left ventricular systolic dysfunction

resting heart rate

QTc interval heart rate variability

Poirier P and Eckel RH: Cardiovascular Complications of Obesity and the

Metabolic Syndrome, In: Cardiovascular Medicine, 200737


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Changes in

CardiacGeometry and

Function TwoYears after

Bariatric Surgery

Owan T et al, JACC 57:732, 201138

Eff t f B i t i S Ph i l


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Effect of Bariatric Surgery on Physical

and ECG ParametersPre

surgeryPost

surgeryp Pre

surgeryPost

surgeryp

Men (n=32) Women (n=68)

Age (year) 4011 439 0.12Weight(kg)

173.141.

2

103.921.

1


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Conclusions

Obesity confers an increased risk for CVD.

Insulin resistance is a major contributor tothe CVD co-morbidities.

Hypertension in particular is a major player. Myocardial dysfunction is common, and is

biventricular and multi-factorial.

Cardiac arrhythmias are present and relate

to many aspects of obesity and its co-

morbidities.40


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Thank You!


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Obesity and Type 2 DiabetesMeeting on Obesity DrugsEndocrinologic and Metabolic Drugs Advisory Comm

March 28, 2012

William C. Knowler, MD, DrPH

National Institute of Diabetes and Digestive and Kidney DisePhoenix AZ, USA


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0

20

40

60

80


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Multicenter randomized clinical trial in U.SMulticenter randomized clinical trial in U.S.

Hypothesis: Type 2 diabetes can beHypothesis: Type 2 diabetes can beprevented or delayed by treating modifiablprevented or delayed by treating modifiabl

risk factorsrisk factors Persons at high risk of type 2 diabetesPersons at high risk of type 2 diabetes

199619962001 with long2001 with long--term followterm follow--up to 201up to 201

Diabetes Prevention Program (DPDiabetes Prevention Program (DP

NEJ M 346: 393346: 393--403, 2002403, 2002

(


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Age >

25 years

Plasma glucose

Fasting 5.3-


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Diabetes Prevention ProgramDiabetes Prevention Program

Eligible participantsEligible participants

Placebo

Metformin

Lifestyle (ILS)Lifestyle (ILS)

Randomized

n = 1082 n = 1073 n = 1079

Total n = 3,2NEJ M 346: 393346: 393--403, 2002403, 2002

M W i h Ch i h DP


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Plac

Met

Life

Mean Weight Change in the DPMean Weight Change in the DP

NEJ M 346: 393346: 393--403, 2002403, 2002

P t d l i di b t

DPP I id f Di b tDPP I id f Di b t


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0 1 2 3 4

0

10

20

30

40Placebo (n=1082)Metformin (n=1073, p


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Diabetes Incidence Rates in DPP

0

4

8

12

PLAC MET ILS

Ca

ses/100p

erson-yr

31% 58%

11.0 7.8 4.8

NEJ M 346:393-403, 2002


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Diabetes Incidence Rates by EthnicityDiabetes Incidence Rates by Ethnicity

The DPP Research Group, NEJ M 346:393-403, 2002

0

4

8

12

White

(n=1768)

African

American(n=645)

Hispanic

(n=508)

American

Indian(n=171)

Asian

(n=142

C

ases/100

person-

yr

Lifestyle Metformin Placebo


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Keys to DPP Lifestyle Success

Weight loss was the key to diabetes preventi

Reduction of total calories, especially fat calo

Achieving 150 minutes of activity each week

DPP: Hazard Rate for Developing Diabetes As


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-15 -10 -5 0 +5

0

5

10

15

20

DPP: Hazard Rate for Developing Diabetes As

A Function of Weight Change From Baseline

Hazardrateper10

0/yr

Mean weight change from baseline (kg)

Average Risk

Intensive Lifestyle Group

Diabetes Care 29: 2102-2107, 2006

Di b t Ri k b W i ht Ch i th D


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-10 -8 -6 -4 -2 0 2 4 6

6

11

16

metformin

placebo

Diabetes Risk by Weight Change in the D

Change from baseline weight (kg)

Diabete

sincide

nce/100

pers-yr

Diabetes 56: 1153-59, 2007

Weight loss explained 64% of the

risk reduction from metformin

(a weight loss drug).

TCF7L2 Genotype and Diabetes


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0

5

10

15

20

Placebo Metformin Lifestyle

Cas

es/100person-

yr

CC CT TT

TCF7L2 Genotype and Diabetes

Incidence in the DPPGenotype at rs79031Genotype at rs79031

(n=3,537)(n=3,537)

DPP Research Group: NEJ M 2006

49% 41% 9%

Oth B fit f DPP Lif t l


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Other Benefits of DPP Lifestyle

Intervention on CVD Risk Factor Lowered blood pressure

Stopped development of new hypertension

Lowered triglycerides

Reduced development of new hyperlipidemia

Lowered CRP and fibrinogen

Reduced incidence of metabolic syndrome

Too few CVD events to evaluate treatment effecDiabetes Care 2005; Diabetes 2005; Ann Internal Med 2005


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DPP Outcomes Study (DPPOS)

2002 2014Masked phase ended, metformin continuedplacebo discontinued, all offered lifestyle.

Weight loss maintenance

Further diabetes incidence

Diabetes complications and death

Long-term effects of DPP interventions o

Lancet 374:1677-1686, 2009

10-Year Weight Change: DPP + DPPOS


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10-Year Weight Change: DPP + DPPOS

Lancet 374:1677-1686, 2009

Cumulative Incidence of Diabetes


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Cumulative Incidence of Diabetes

Lancet 374:1677-1686, 2009

Mean Weight Changes (kg) Since Randomization by Age


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0 1 2 3 4 5 6 7 8 9

-8

-6

-4

-2

0

2

C. Age Group 25 - 44 y

Year since DPP Randomization

ChangeinWeight(kg)

Placebo Metformin

0 1 2 3 4 5 6 7 8 9

-8

-6

-4

-2

0

2

G. Age Group: 60 y


ChangeinWeight(kg)

Placebo Metformin

0 1 2 3 4 5 6 7 8 9 10

-8

-6

-4

-2

0

2

E. Age Group: 45 - 59 y


ChangeinWeight(kg)


0 1 2 3 4 5 6 7 8 9 10

-8

-6

-4

-2

0

2

A. All Participants


ChangeinWeight(kg)


All ages

Age 45-59

Age 25-44

Age

60



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Micro-

and MacroVascular

Outcomes in the DPPOS?Expected in 2014

10-year Costs of Treatment and Outs


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Medical Care in the DPP/DPPOS

Diabetes Care 35: 723-730, 2012



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Diabetes Care 35: 723-730, 2012



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Diabetes Care 35: 723-730, 2012



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Diabetes Care 35: 723-730, 2012



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Diabetes Care 35: 723-730, 2012

Weight Loss with Lifestyle Counseling


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g y g

and Placebo

or Orlistat

(XENDOS)

3,277 obese nondiabeticadults

-12

-9

-6

-3

0

0 1 2 3 4

Years from Randomization

Weightloss(kg) Placebo (34% compl.) Orlistat (52% compl.)

Torgerson JS: Diab. Care, 2004

Diabetes Incidence with Lifestyle CounselinDiabetes Incidence with Lifestyle Counselin


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abetes c de ce t esty e Cou seyand Placebo orand Placebo orOrlistatOrlistat

in IGT (XENDOS)in IGT (XENDOS)

0

2

4

6

8

10

0 1 2 3 4

Years from Randomization

Cum

ulativeIncidence(%)

Placebo (34% compl.) Orlistat (52% compl.)

HRR = 0.63

(95%CI = 0.46

0.86)

p


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Prevention or Delay of Type 2 Diabetewith Drugs or Lifestyle Intervention

Several other clinical trials with similar results

Little evidence for long-term non-glycemic outcome


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Early Life Predictors of

Obesity and Diabetes:The Pima Indian Longitudinal Stu

Relative Body Weight in Children


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y g by Maternal Diabetes

100

110

120

130

140

150

Birth 5-9 10-14 15-19

Age (years)

Mean%DesirableW

eight

Diabetic

Prediabetic

Nondiabetic

Mother During Pregnancy

Pettitt: NEJM 1983

Diabetes in Offspring By MaternalDiabetes in Offspring By Maternal


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0

20

40

60

5-9 10-14 15-19 20-24 25

Age (years)

Prevalence(%

)

nondiabeticprediabeticdiabetic

Diabetes in Offspring By MaternalDiabetes in Offspring By MaternalDiabetes in PregnancyDiabetes in Pregnancy

Mother during pregnancyMother during pregnancy

Updated from Pettitt: Diabetes, 1988

1010--Year Diabetes Incidence by Relative Weight, FasYear Diabetes Incidence by Relative Weight, FasI li d 2I li d 2 h Gl i 15h Gl i 15 19 Y19 Y ld Pi I dld Pi I d


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0

5

10

15

20

25

Relative Weight Fasting Insulin 2-h Gluco

Incidence(%)

low middle hig

Insulin, and 2Insulin, and 2--hr Glucose in 15hr Glucose in 15--19 Year19 Year--old Pima Indold Pima Indwithwith >>

1 Diabetic Parent*1 Diabetic Parent*

TertileTertile

GroupsGroups

McCanceMcCance:: DiabetologiaDiabetologia, 1994, 1994* Incidence = zero if both parents nondiabeti

Diabetes in Pregnancy and Offspring:


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Pregnant WomanPregnant Woman

with Diabeteswith Diabetes

Young WomanYoung Woman

with Diabeteswith DiabetesInfant (daughter)Infant (daughter)

of Diabetic Motherof Diabetic Mother

g y g

The Vicious Cycle

PettittPettitt & Knowler,& Knowler,

JJ ObesObes WtWt RegReg 19881988

Conclusions


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Conclusions

Overweight / obesity strongly related to type 2 diab

Metformin & lifestyle interventions in adults can red Weight

Incidence of diabetes

Health care costs Incidence of diabetes complications and CVD ?

Early life conditions influence obesity and diabetes

Body weight can be reduced by many means (with

without drugs), but maintenance is difficult


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There are many waysto treat obesity

If many cures are offered for an illness, yo

may be sure that the illness has no cure.

Anton Chekhov: The Cherry Orchard, 1904


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Look AHEAD (Action for Health

in Diabetes) Trial

Rena R. Wing, Ph.D.Professor of Psychiatry & Human Behavior

Warren Alpert Medical School of Brown UniversityDirector, Weight Control & Diabetes Research Center

The Miriam Hospital

Providence, Rhode Island


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2


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OverviewOverview

Rationale and designRationale and design

Year 4 results: changes in weight and fitnessYear 4 results: changes in weight and fitness

Year 4 results: changes in cardiovascularYear 4 results: changes in cardiovascular

disease (CVD) risk factorsdisease (CVD) risk factors

3


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A multicenter, randomized clinical trialA multicenter, randomized clinical trial

examining the longexamining the long--term effects (up to 13.5term effects (up to 13.5

years) of an intensive lifestyle interventionyears) of an intensive lifestyle intervention

program on cardiovascular morbidity andprogram on cardiovascular morbidity andmortality in overweight or obese personsmortality in overweight or obese persons

with Type 2 Diabetes.with Type 2 Diabetes.

4


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Funding SourcesFunding SourcesNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of Diabetes and Digestive and Kidney Diseases

National Heart, Lung, and Blood InstituteNational Heart, Lung, and Blood Institute

National Institute of Nursing ResearchNational Institute of Nursing Research

National Center on Minority Healthy and Health DisparitiesNational Center on Minority Healthy and Health Disparities

Office of Research on Women's HealthOffice of Research on Women's Health

Centers for Disease Control and PreventionCenters for Disease Control and Prevention

5


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Benefits ofBenefits of

Weight LossWeight Loss Weight loss is strongly recommended forWeight loss is strongly recommended for

overweight patients with Type 2 diabetesoverweight patients with Type 2 diabetes

Short term (Short term (


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Lack of Data onLack of Data on Long Term BenefitsLong Term Benefits

No randomized trials have been conducted toNo randomized trials have been conducted todetermine long term consequences of intentionaldetermine long term consequences of intentionalweight lossweight loss

Surgical studies suggest positive effects of largeSurgical studies suggest positive effects of largeweight lossesweight losses

However, some observational studies suggestHowever, some observational studies suggestthat weight loss or weight cycling is associatedthat weight loss or weight cycling is associated

withwith increasedincreased morbidity/mortalitymorbidity/mortality7


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Look AHEAD is a multicenter RCTLook AHEAD is a multicenter RCT

examining theexamining the longlong--term effectsterm effects (up to(up to

13.5 years) of an13.5 years) of an intensive lifestyleintensive lifestyle

intervention program to produceintervention program to produce weightweight

loss and increase physical activityloss and increase physical activity ononcardiovascular morbidity and mortalitycardiovascular morbidity and mortality

inin

over 5,000 overweight or obese personsover 5,000 overweight or obese personswithwith type 2 diabetestype 2 diabetes..

8

R d i d St d A


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Randomized Study Arms

Intensive lifestyle intervention (ILI)

Diabetes support and education (DSE)

(usual care control group)

9

Primary HypothesisPrimary Hypothesis


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The ILI, as compared to DSE, will reduce the

incidence rate of an aggregate endpoint of CVDdefined as including:

cardiovascular death (fatal myocardial infarction

and stroke) non-fatal myocardial infarction

non-fatal stroke

hospitalization for angina

over 13.5 yr. follow-up.10

S d O tSecondary Outcomes


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Secondary OutcomesSecondary Outcomes

Composite #1Composite #1

CVD deathCVD death NonNon--fatal MIfatal MI

NonNon--fatal strokefatal stroke


AllAll--cause deathcause death

NonNon--fatal MIfatal MI


Hospitalization forHospitalization foranginaangina


AllAll--cause deathcause death NonNon--fatal MIfatal MI


Hospitalization for anginaHospitalization for angina Hospitalization for CHFHospitalization for CHF

Coronary artery bypassCoronary artery bypass

grafting (CABG) orgrafting (CABG) orangioplastyangioplasty

Carotid endarterectomyCarotid endarterectomy

Peripheral vascular diseasePeripheral vascular disease11

Other Outcomes


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Other Outcomes

Cardiovascular disease risk factors

Diabetes control and complications

General health

Hospitalizations Quality of life and psychological outcomes

Costs and cost effectiveness

12


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Eligibility CriteriaEligibility Criteria

Type 2 diabetesType 2 diabetes

Overweight (BMIOverweight (BMI >> 25 kg/m25 kg/m22

oror>> 27 kg/m27 kg/m22

if on insulin)if on insulin) Age 45Age 45--75 years75 years

> 33% minorities> 33% minorities

With or without history of CVDWith or without history of CVD

BP < 160/100 mmHgBP < 160/100 mmHg

HbA1c < 11%HbA1c < 11% Triglycerides < 600 mg/dlTriglycerides < 600 mg/dl

< 30% using insulin< 30% using insulin

13

Baseline Characteristics of ParticipantsBaseline Characteristics of Participants


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LifestyleLifestyle DSEDSE(N=2570)(N=2570) (N=2575)(N=2575)

WomenWomen59%59% 60%60%

MinorityMinority 37%37% 37%37%

Age (years)Age (years) 58.658.6 58.958.9

Insulin UsersInsulin Users 15%15% 16%16%

Baseline BMIBaseline BMI 35.935.9 36.036.0

Baseline Weight (kg)Baseline Weight (kg) 100.6100.6 100.9100.9Baseline Waist (cm)Baseline Waist (cm) 113.8113.8 114.1114.1

History of Prior CVD EventHistory of Prior CVD Event

15%15% 14%14%14

Intensive Lifestyle InterventionIntensive Lifestyle Intervention


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Intensive Lifestyle InterventionIntensive Lifestyle Intervention

Weekly for 6 monthsWeekly for 6 months

3x per month for 6 months3x per month for 6 months2x per month from year 2 to end2x per month from year 2 to end

Group plus individual sessionsGroup plus individual sessions

Diet , physical activity, and behavioralDiet , physical activity, and behavioral

strategiesstrategiesLook AHEAD Research Group. Diabetes Care, 2007;30:1374-83.

15

RecommendationsRecommendations


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RecommendationsRecommendations

Weight LossWeight Loss

Lose 10% of body weight and maintainLose 10% of body weight and maintain

Dietary IntakeDietary Intake

12001200--1500 kcal/day < 250 lb1500 kcal/day < 250 lb

15001500--1800 kcal/day1800 kcal/day >> 250 lb250 lb


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Diabetes Support and

Education (DSE)

33--4 meetings / year4 meetings / year To promote retentionTo promote retention

Health education topicsHealth education topicsDietDiet

ExerciseExerciseSocial SupportSocial Support

17


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Medication AdjustmentsMedication Adjustments Made by participant's own physicianMade by participant's own physician

Study protocol for adjusting diabetesStudy protocol for adjusting diabetes

medications during initial weeks ofmedications during initial weeks of

interventionintervention

18

St d D iSt d D i


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Study DesignStudy Design

90% power to detect an 18% reduction in CVD events90% power to detect an 18% reduction in CVD events

over 10.5 years of followover 10.5 years of follow--upup

AssumedAssumed 3.125% CVD event rate in control3.125% CVD event rate in control

ActualActual 0.7% CVD event rate in control at 30.7% CVD event rate in control at 3 yearsyears

Convened Endpoint Working GroupConvened Endpoint Working Group(masked to study results)(masked to study results)

19


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Why Low Event Rate?Why Low Event Rate? Secular trendsSecular trends

Trial participants healthier then cohortTrial participants healthier then cohort

studiesstudies

Graded exercise testGraded exercise test

20


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Changes to Study DesignChanges to Study Design Extended study duration by 2 yearsExtended study duration by 2 years

(11.5 to 13.5 years)(11.5 to 13.5 years)

Broadened definition of primaryBroadened definition of primary

endpoint to include hospitalized anginaendpoint to include hospitalized angina

21

Brancati, et al. Clinical Trials, 2012, 9; 113Brancati, et al. Clinical Trials, 2012, 9; 113--124124



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The ILI, as compared to DSE, will reduce the

incidence rate of an aggregate endpoint of CVDdefined as including:

cardiovascular death (fatal myocardial infarction

and stroke) non-fatal myocardial infarction

non-fatal stroke

hospitalization for angina

over13.5 yr. follow-up.22


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Year 4 Results:Year 4 Results:Changes in Weight andChanges in Weight and

FitnessFitness

23

Year 4 RetentionYear 4 Retention


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Year 4 RetentionYear 4 Retention

DSEDSE ILIILI

Randomized, NRandomized, N 2,5752,575 2,5702,570

Seen Year 4*Seen Year 4*

% of randomized% of randomized

% of current cohort% of current cohort

2,4032,403

(93.3%)(93.3%)

(95.8%)(95.8%)

2,4202,420

(94.2%)(94.2%)

(96.5%)(96.5%)

*Outcomes assessment and/or weight measurement

24

Percent Weight Change from Baseline


101/186

Repeated Measures Adjusted for Clinic and Baseline Level

Average effect across all visits: -

5.27, p


102/186

Percentage of Participants in ILI and DSEPercentage of Participants in ILI and DSE

Who Met Different Weight Loss Criteria atWho Met Different Weight Loss Criteria atYear 4Year 4

DSE ILI

Any weight loss (vs. gain) 55% 74%

5% weight loss 25% 46%

10% weight loss 10% 23%

26

Percent Fitness Change from Baseline


103/186

Repeated Measures Adjusting for Clinic and Baseline Level

Average effect across all visits: 10.78, p


104/186

Year 4 Weight LossYear 4 Weight Loss

Percen

tweight

loss

Perce

ntweightloss

NS NS

28

4-Year Weight Loss Outcomes


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-6

-5

-4

-3

-2

-1

0

Overweight

Class I

Class IISevere

C

hangeinb

odyweigh

t(%)

*

* Overweight significantly different from all other groups (p


106/186

Year

0

2

4

6

8

10

12

0 1 2 3 4

AmericanIndian/ Other

AfricanAmerican

Hispanic

Non-Hispanic White

%Reductionin

InitialW

eight

Losses across Race/Ethnicity Groups

30

Oldest Participants Lost Significantly More than


107/186

0

2

4

6

8

100 1 2 3 4

Year

45-54 yr

55-64 yr

65-76 yr

%Red

uctionin

InitialWeight

Younger Participants at all Assessments

31

Success of Those Aged 65Success of Those Aged 65 74 is74 is


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Success of Those Aged 65Success of Those Aged 65

74 is74 is

Related to Better AdherenceRelated to Better Adherence

Treatment

Contact inYear 1

Treatment

Contact inYears 2

4

Activity

(kcal/week)Year 4

Calorie

IntakeYear 4

Age

45

54 35 18 1179 1695

55

64 35 21 1247 1621

65

74 37 22 1337 1465

32

Four-Year Weight Loss Trajectories of 887 ILI Participants

Who Had Lost 10% Initial Weight at Year 1


109/186

N=174

(19.6%)

+2

024

68

10

1214

16

181 2 3 4

PercentageW

eightLoss

Who Had Lost

10% Initial Weight at Year 1

Years

0-5%

5-6.9%

7-

10%

10%

Gained

N=374

(42.2%)

N=152

(17.1%)

N=99

(11.2%)

N=88

(9.9%)

+4

33

Mean Annual Number of Treatment Sessions Attended in Years 2-4 for

Participants Who Had Lost > 10% at Year 1

(by Category of Weight Change at Year 4)


110/186

(by Category of Weight Change at Year 4)

0

5

10

15

20

25

10% 5 - 9.9% 0 - 4.9% Gained

Treatment

Sessions

Weight Change at Year 4

23.6 22.7 18.5 16.8

p < .0001 p < .0001

34


111/186

Variables Associated with PercentVariables Associated with Percent


112/186

Weight Losses at Year 4Weight Losses at Year 4

Variable VarianceExplained

Baseline weight, gender, age, ethnicity, insulin 2.59%

Treatment attendance 4.0%

Dietary intake or physical activity 1.7

1.8%

Year 1 weight loss 21.9%

36

Conclusions :Conclusions :

Ch i W i ht d FitCh i W i ht d Fit


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Changes in Weight and FitnessChanges in Weight and Fitness ILI produced significantly greater changes in weight andILI produced significantly greater changes in weight and

fitness than DSE through 4 yearsfitness than DSE through 4 years

Nearly 50% of ILI participants have maintained a lossNearly 50% of ILI participants have maintained a loss 5% of initial weight at year 4.5% of initial weight at year 4.

The intervention produced clinically significant weightThe intervention produced clinically significant weight

loss in all subsets of a demographically and ethnicallyloss in all subsets of a demographically and ethnicallydiverse population.diverse population.

The best predictors of longThe best predictors of long--term weight loss were:term weight loss were:

Adherence to diet and exercise recommendationsAdherence to diet and exercise recommendations Initial weight lossInitial weight loss

Look AHEAD Research Group. Arch Int Med 2010;170:1566-75

37


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Year 4 Results:Year 4 Results:Changes in CVD RiskChanges in CVD Risk

FactorsFactors

38

HbA1c Change from Baseline


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Repeated Measures Adjusting for Clinic and Baseline LevelAverage effect across all visits: -0.27, p


116/186

y gy g

YearNo Baseline Use Baseline Use

DSE

N=348

ILI

N=354 p-value

DSE

N=2208

ILI

N=2202 p-value

1 33% 10%


117/186

Use of Any Insulin

Year

No Baseline Use Baseline Use

DSEN=2167

ILIN=2190 p-value

DSEN=408

ILIN=380 p-value

1 4% 2%


118/186

Prevalence of Achieving ADA Goal for HbA1c < 7.0%

Year DSE ILI P-value

Baseline 45% 47% NS

Year 1 50% 72%


119/186

DBP (mmHg) Change from Baseline


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Repeated Measures Adjusting for Clinic and Baseline LevelAverage effect across all visits:-0.43, p=0.01

DSE

(mmHg)

ILI

(mmHg)

P-

value

Baseline 70.37 69.93 NS

Y1

BL - 1.64 - 3.07


121/186

Antihypertensive DrugAntihypertensive Drug

YearNo Baseline Use Baseline Use

DSE

N=684

ILI

N=661 p-value

DSE

N=1872

ILI

N=1895 p-value

1 22% 16% 0.01 95% 94% 0.43

2 32% 25% 0.005 96% 94% 0.002

3 40% 33% 0.01 95% 94% 0.23

4 47% 43% 0.17 95% 94% 0.58


45

P l f A hi i ADA G l f BP


122/186

Prevalence of Achieving ADA Goal for BP


123/186

47

Average effect across all visits: 1.70, p


124/186

( g ) g

Repeated Measures Adjusting for Clinic and Baseline Level

Average effect across all visits: 1.57, p=0.009

DSE

(mg/dl)

ILI

(mg/dl)

P-value


Y1

BL - 5.50 - 5.11 0.60

Y2

BL -

11.10 - 9.43 0.05

Y3

BL -

16.00 -

13.88 0.01

Y4

BL -

18.75 -

16.64 0.01

LD

Lchangefrombaseline(mg/dl)

-30

-20

-10

0

0 1 2 3 4

Year

DSE

ILI

48


125/186

LDL Cholesterol (mg/dl) Change from Baseline

Repeated Measures Adjusting for Clinic, Baseline Level,


126/186

p j g , ,

and Medication Use Average effect across all visits: 0.47, p = 0.42

DSE

(mg/dl)

ILI

(mg/dl)

P-value


Y1

BL - 3.70 - 4.44 0.33

Y2

BL - 7.62 - 7.47 0.85

Y3

BL -

12.02 -

10.64 0.08

Y4

BL -

13.52 -

12.45 0.19

LD

Lchangefro

mbaseline(mg/dl)

-16

-14

-12

-10

-8

-6

-4

-2

0

0 1 2 3 4

Year

DSE

ILI

50


127/186

Prevalence of Achieving ADA Goal for LDL-C


128/186


129/186

53


130/186

54


131/186

55

Conclusions :Conclusions :

Changes in CVD Risk FactorsChanges in CVD Risk Factors


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ILI has produced sustained improvements inILI has produced sustained improvements in

glycemicglycemic control, SBP, and HDLcontrol, SBP, and HDL--C as comparedC as compared

to DSE.to DSE.

LDLLDL--C improved more in DSE than in ILI due toC improved more in DSE than in ILI due to

increasedincreased statinstatin use; after adjusting foruse; after adjusting formedications, changes in LDLmedications, changes in LDL--C did not differC did not differ

significantly between groupssignificantly between groups

Modest weight losses improved CVD risk factors,Modest weight losses improved CVD risk factors,with the exception of LDLwith the exception of LDL--CC


Changes in CVD Risk FactorsChanges in CVD Risk Factors

56

Implications for FDAImplications for FDA


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Intensive lifestyle interventions can produce sustainedIntensive lifestyle interventions can produce sustainedbenefits for weight and fitness across diverse age,benefits for weight and fitness across diverse age,

gender, ethnic/racial groups and weight categoriesgender, ethnic/racial groups and weight categories

Initial weight loss and adherence are the strongestInitial weight loss and adherence are the strongest

predictors of long term weight losspredictors of long term weight loss

Modest weight losses can produce sustainedModest weight losses can produce sustained

improvements inimprovements in glycemicglycemic control, SBP, and HDLcontrol, SBP, and HDL--CC

Look AHEAD will continue to follow participants toLook AHEAD will continue to follow participants to

determine the longdetermine the long--term impact of intensive lifestyleterm impact of intensive lifestyle

intervention on CVD morbidity and mortalityintervention on CVD morbidity and mortality57

Percentage of Participants in ILI and DSE

Groups Who Met Different Weight Loss Criteria

at Year 4


134/186

8%

Look AHEAD Research Group, 2011

Intensive Lifestyle Intervention (ILI)

Diabetes Support & Education (DSE)

0

10

20

30

40

50

60

70

80

90

100

> 0

%

10 %

5 %

7

%

74%

55%

46%

25%

35%

18%10%

23%

%ofPa

rticipants

5 %

0%

18%

26%

45%

15 %

4%9%

Weight Gain Weight Loss

at Year 4

58

Food and Drug Administration

Washington DC

March 28-29 2012


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Drugs to Treat Obesity:

Cardiovascular and Other Risks

George A. Bray, MD,MACP, MACE

Boyd ProfessorPennington Center

Baton Rouge, LA

March 28 29, 2012

1


136/186

Disclosures

Consultant to Takeda Global

Development

Nutrition Advisory Board for Herbalife

Advisor to Buckapound

2

Structure of My Presentation


137/186

y

Obesity is a risk to life and health for

many people Weight loss reduces these risks

We need drugs for weight loss because

they enhance the effects of lifestyle

All drugs have risks; those associated

with anti-obesity drugs are of many kinds

We can mitigate these risks

3

Obesity Increases Risk of


138/186

Mortality and Morbidity

4

Risk Increases as BMI Rises


139/186

64

15 20 25 30 35 40 45Body Mass Index

32

16

8

YearlyDeaths

per1000(99%CI)

Male

Female

Relative Risks at

ages 35-89

adjusted for age,

smoking and

study. Floated

data to make

weighted average

match weighted

mortality at ages

35-79 Pooled Data

from 57 studies.

First 5 years of

follow-up are

excluded.

Whitlock G Prospective Studies

Collaboration Lancet. 2009 Mar 28;373(9669):1083-96.

5

Disease-Specific Increase inMortality Rate per 5 BMI Units


140/186

y p

Overall mortality 30%

Diabetes mellitus 116%

Hepatic disease 80%

Renal disease 60%

Vascular disease 40%

Malignancy 10%

Whitlock G Prospective StudiesCollaboration Lancet. 2009 Mar 28;373(9669):1083-96. 6

Medical Complications of ObesityIdiopathic intracranial hypertension


141/186

Phlebitisvenous stasis

Coronary heart disease

Pulmonary diseaseabnormal function


hypoventilation syndrome

Gall bladder disease

Gynecologic abnormalities

abnormal menses

infertility

polycystic ovarian syndrome

Gout

Stroke

Diabetes

Osteoarthritis

Cancer

breast, uterus, cervix

colon, esophagus, pancreaskidney, prostate

Nonalcoholic fatty liver diseasesteatosis

steatohepatitis

cirrhosisHypertension

Dyslipidemia

Cataracts

Skin

Idiopathic intracranial hypertension

Severe pancreatitis

7

Risks Are Related to Fat Mass and

Metabolic Effects of Obesity


142/186

Metabolic Effects of Obesity

Excess fat

stores

GenesEnvironment

Activity Food Intake

Metabolic

Diseases

Stigma

Sleep

apnea

OsteoarthritisDiabetes

GB Disease

NAFLD CVD

Cancer

Weight-Related

Diseases

Bray GA J Clin Endocrinol Metab. 2004 Jun;89(6):2583-9.8

BMI Has Biggest Effect on Diabetes


143/186

BMI, body mass index.

Willett WC et al. N Engl J Med. 1999;341(6):427434.

BMI (kg/m2)

Relat

iveRisk

Women Men

4

6

5

3

2

1

0


144/186

& Risk of Cancer and Diabetes

10

Surgical Weight Loss Reduces


145/186

Sjostrom L, et al. N Engl J Med. 2007;357(8):741-752.

Mortality SOS Study1412

10

8

6

4

2

0

Cumu

lative

Morta

lity(%)

Years

0 2 4 6 8 10 12 14 16

Control

SurgeryP=0.04

No. at Risk

Surgery 2010 2001 1987 1821 1590 1260 760 422 169Control 2037 2027 2016 1842 1455 1174 749 422 156 11

Incidence of myocardial infarction (MI)


146/186

Log-rank test P=0.039

Unadj. HR=0.58

95% CI: 0.34-0.979

Adj HR=0.52

95% CI: 0.31-0.89

P=0.02

0.000

0.005

0.010

0.015

0.020

0.025

Kaplan-Me

iercumulative

inc

idence

2010 1970 1557 412Surgery

2037 1993 1423 405Control

Number at risk

0 2 4 6 8 10 12 14 16 18

Follow-up time, years

Control (37 events)Surgery (22 events)

Fatal MI

Log-rank test P=0.304

Unadj. HR=0.88

95% CI: 0.69-1.12

Adj. HR=0.71

95% CI:0.54-0.94

P=0.02

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

2010 1943 1502 390Surgery

2037 1958 1369 384Control

0 2 4 6 8 10 12 14 16 18

Control (136 events)Surgery (122 events)

Total MIin the SOS control and surgery group

Sjstrm L, et al: JAMA 2012; 307:56-65

Follow-up time, years

Kaplan-Me

iercumulative

incidence

12

P=0.02P=0.02

Cardiometabolic Risk is Reduced40

50


147/186

No. of subjects

TG

-100-40 -30 -20 -15 -10 -5 0 5 40

89 82 133 71 66 67 127 121

-80

-40

0

40

Insulin

Body weight changes (kg)

Riskfactorchanges

(%)

-30

-15

89 82 133 71 66 67 127 121 86No. of subjects

Uric acid

-100-40 -30 20 15 10 -5 0 5 40

0

15

Glucose

HDLCHOL

-100 -40 -30 -20 -15 -10 -5 0 5 40-100

0

25

-10

-5

0

5

89 82 133 71 66 67 127 121 86.

SBP

-100 -40 -30 -20 -15 -10 -5 0 5 40SjSjstrstrm CD et al.m CD et al. Obes Res.Obes Res.

1997;5:5191997;5:519--530.530.

DBP

No. of subjects

There Are Other Important


148/186

Benefits of Weight Loss

14

Scoring for Change in MobilityStage


149/186

1 2 3 4

Vigorous Activity

Walking- 1 mi

Bending

Walking 1 block

Moderate activity

Climbing 1 flight

0 1 0 1 0 1 0 1Rejeski J et al NEJM 2012;March 29; with approval; on-line after 5 PM March 28 NEJM.org

15

Effect of Age and Weight Loss on


150/186

Mobility

Rejeski J et al NEJM 2012;March 29; with approval; on-line after 5 PM March 28 NEJM.org

1

0.8

0.6

0.4

0.2

01 2 3 4

Time

Diabetes Support

and Education

M

obilityS

core

1

0.8

0.6

0.4

0.2

01 2 3 4

Time

Intensive Lifestyle

Intervention

M

obilityS

core

Sleep Disordered Breathing in Obese

Patients with Type 2 Diabetes (N=305)


151/186

AHI < 5

AHI 5-14.9AHI 15-29.9

AHI > 30

13.4% No

Obstructive

Sleep Apnea

33.5 %Mild

30.5%

Moderate

22.6%Severe

Patients with Type 2 Diabetes (N 305)

Foster et al. Diabetes Care. 2009 Jun;32(6):1017-9.17

Changes in Weight and AHI over 4 yr


152/186

Change in Weight (Kg) Change in AHI

0

4

8

-4

-8

-12

0

4

8

-4

-8

-120 1 2 4 0 1 2 4

Year Year -- DSE -- ILI

DSE

DSE

ILI

ILI


153/186

Orlistat Enhances Weight LossAbove Lifestyle/Placebo


154/186

SB DB DB

Mildly hypocaloric diet Weight maintenance

(eucaloric diet)

-0

-1

-2

-3

-4

-5

-6

-7

-8

-9-10

-11

-12

-10 0 10 20 30 40 50 60 70 80 90 100 110

Week%

Changein

bodywei

ght(SE)

Placebo tid

Orlistat 120 mg tid

y

Sjostrom, L et al Lancet, 1998;132:167-172

How Much Weight Loss Is Needed


155/186

to Prevent Type 2 Diabetes?

Change in Weight From Baseline (kg)

0-10 -5 +5

IncidenceRate

per100Person-Years

10

20

15

5

0

Preferred Adequate

0

Redrawn from: Hamman, et al Diabetes Care 29:2102-2107, 2006 21

Medications Produce More

Weight Loss Than Lifestyle


156/186

g y0

-2

-4

-6

-8

-10

Treatment Control Lifestyle Lifestyle Orlistat

+ PlaceboAdapted from LeBlance et al Ann Int Med 2011;155:434-447

W

eightLo

ss

(kgor

%)

Weighted Mean Differences:-3.01 (-402, -201) -2.98 (-3.92, -2.05)

22

How Do Drugs Stack-Up?Drug # Studies Length Wt Loss


157/186

Phentermine 6 13 wks -6.4 kg

Diethylpropion 9 18 wks -6.5 kg

Mazindol 22 11 wks -5.7 kgOrlistat 15 > 1 yr -5.3kg

Fluoxetine 6 24 wks -4.8 kg

Bupropion 2 24 wks -8.0 kg

Pramlintide 1 1 yr -9.0 kg

Exenatide 12 24 wks -2.9 kgLiraglutide 8 24 wks -2.8 kg

Metformin 3 1 yr -2.8 kg*

Adapted from Vilsboll T et al BMJ 2012;344:1-11; LeBlanc ES et al Ann Int Med

2011;155:434-447 Hainer V. et al Diabet/Metab Res Rev 2012: in press23

How Do Drugs Stack-Up?Drug # Studies Length Wt Loss


158/186

Sibutramine 10 > 1 yr -6.4 kg

Rimonabant 4 > 1 yr -6.3 kg

Lorcaserin 2 1 yr -5.8 kgCetilistat 1 12 wks -4.1 kg

Tesofensine 1 6 mos -11.3 kg

Phen/Fenfluramine 1 34 wks -14.2 kg

Phen/Topiramate 2 > 1 yr -10.2 kg

Buprop/Naltrex 2 > 1 yr -8.7 kg

Pram/Phentermine 1 24 wks -11.3 kg

Pram/Leptin 1 24 wks -11.5 kg

Adapted from Vilsboll T et al BMJ 2012;344:1-11; LeBlanc ES et al Ann Int Med

2011;155:434-447 Hainer V. et al Diabet/Metab Res Rev 2012: in press24

Change in Hemoglobin A1c Change in Fasting Glucose

Surgery Is Superior to MedicalTherapy for Weight Loss in Diabetes


159/186

25

Change in Hemoglobin A1c

Months

HemoglobinA1c(%)

0 3 6 9 125

6

7

8

9

10

Med Therapy

Gastric Bypass

Sleeve

Change in Fasting Glucose

Months

FastingG

lucose(mg/dl)

0 3 6 9 120

50

100

150

200

250

Med Therapy

Gastric Bypass

Sleeve

Change in Number ofAnti-Diabetic Medicatios

Months

NumberofAnti-d

iabetic

Medications

0 3 6 9 12

0

1

2

3

4

Med Therapy

Gastric Bypass

Sleeve

Change in BMI

Months

BMI(kg/m

2)

0 3 6 9 12

20

25

30

35

40

Med Therapy

Gastric Bypass

Sleeve

Schauer P. et al NEJM 2012; March 26


160/186

What Predicts Weight Loss?

26

Answer: Initial Weight loss

One Year Weight Loss Predicted


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> 5% weight loss at 3 months with Orlistat

predicted weight loss and improvedcardiovascular risks at one year.

> 2 to 4 kg weight loss with Sibutraminepredicted 1 year weight loss: > 2 kg in first month or

> 4 kg at 3 months

27

by Initial Weight Loss

Bray GA , Guide to Obesity and the Metabolic Syndrome, 2011; Finer N, et al Diab Obes

Metab 2006;8:206-; Rissanen A et al IJO 2003;27:103-109; Toplak H et al Diab Obes

Metab 2006;699-708

Weight Loss at One Year Based


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28

on Weight Loss at 3 Months

Months

Mean%WeightLoss

0 2 4 6 8 10 12-15

-10

-5

0

< 4 kg

> 4 kg

Finer N, et al Diab Obes Metab 2006;8:206-213.

BUT All Drugs Have Adverse


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Events and Some Can Be Serious

29

Unintended Consequences of DrugTreatment for Obesity


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Year Drug Consequence

1892 Thyroid Hyperthyroidism

1932 Dintrophenol Cataracts/Neuropathy1937 Amphetamine Addiction

1968 Aminorex Pulmonary Hypertension

1997 Phen/Fenfluramine Valvulopathy

1998 Phenylpropanolamine Strokes

2003 Ma Huang (ephedra) Heart attacks/stroke

2007 Ecopipam (Dopamine) Depression/Suicide

2008 Rimonabant (CB-1) Depression

2010 Sibutramine CVD RiskBray GA Battle of the Bulge, Dorrance Publishing 2007 p. 59

30

Would an Outcome Study Reduce


165/186

these Adverse Events?Adverse Event Drugs

Idiopathic Primary

Pulmonary Hypertension

Aminorex

Fenfluramine

Pointes-de-Torsade

Arrhythmia

Collagen-based low

calorie diets

Valvular insufficiency Fenfluramine,

dexfenfluramine

Suicidality Rimonabant

Ecopipam

Stroke Phenylpropanolamine

Cardiovascular disease Ephedra; sibutramine 31

Adverse Event Profile (Odds-Ratio)

Adverse Event ORL FLUOX BUPROP TOP


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Diarrhea/Constipation 54.8 1.85 1.37 1.08

Headache 1.18 1.35 0.99 --

Nausea 0.95 3.27 -- --

Fatigue -- 2.83 -- 1.36

Dry Mouth -- -- 3.26 3.13

Nervous - CNS -- 7.85 0.98 3.97

Depression 0.33 -- -- --

Paresthesias -- -- -- 20.2Taste Change -- -- -- 11.1

Upper Respiratory -- -- 1.22 1.76

Adapted from, Li , Z et al. Ann Int Med 2005;142:532-54632

Outcomes Differ Between Drugs


167/186

Outcome - Change ORL SIB RIM

Waist Circumference -2.06* -3.99* -3.89*

Systolic BP -1.52* 1.69* -1.78*

Diastolic BP -1.38* 2.42* -1.23*

Heart Rate -- 4.53* --

Total Cholesterol -0.32* -- -0.04

LDL-cholesterol -0.26* -- -0.05

HDL-cholesterol -0.03* 0.04* 0.10*Triglycerides -0.03 -0.18* -0.24*

Adapted from Rucker D, et al BMJ 2007335:1194-1199

Data are weighted mean differences;

* = Confidence intervals do not cross 0 33

Sibutramine Reduces Weight, But


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Increases Blood Pressure:The Sibutramine Cardiovascular

Outcome (SCOUT) Trial

34

Outline of SCOUT Trial


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Randomization

Sibutramine 10 mgSibutramine 10 mg or 15 mg

Lifestyle and Placebo

Treatment Period

Up to 6 Years

Monthly visits for first 3 mosFollowed by 3 monthly visits

Beginning with Month 6

Randomized Phase

Follow-up Period

Contact with site

Every 3 months

6-week

Lead-inScreening

Lead-in

Period

Baseline

Final

Visit

James WP et al NEJM 2010363:9-5-91; Caterson I et al Obesity 2010;18:987-99435

Weight Loss during the SCOUT Trial


170/186

-4 0 4 8 12 16 20 24

90

95

100

Lifestyle

Sibutramine

intervals of Treatment

BodyW

eight(kg)

James PT et al NEJM 2010; 363:9-5-917; FDA Briefing Document 15 Sept 2010 36

Primary Outcome Endpoint ITT


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AnalysisPrimary Endpoint

Nonfatal MI

Nonfatal StrokeResuscitation after

cardiac arrest

Cardiovascular death

18

Inc

idenceo

fPrimary

Ou

tcome

Even

ts(%

)

Months Since Randomization

0 6048362418

16

1412

10

86

4

2

0

Sibutramine

Placebo

11.4%

10.0%

Kaplan-Meier Plot of Weight Loss

S


172/186

by Response to Sibutramine

0 20 40 60

Months Since Randomization

0

2

14

12

10

4

6

8

Inc

idenceo

fPrima

ry

Ou

tcom

eEvent

SCOUT Study

comparing the30% of patients

randomized to

sibutraminewho lost >5% of

their body

weight againstthe 70% who

lost < 5%

Sibutramine

> 5% Loss

Sibutramine

< 5% Loss

9.5%

14.0%

How Can We Mitigate the Risk

f W i h L D ?


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from Weight Loss Drugs? Develop drugs with high safety profile

Use drugs intermittently or for short intervals Use combinations of drugs

Establish that weight loss continues Select drugs that cause weight loss when

treating overweight patients for conditions

other than obesity Only treat patients who respond

39

0

Intermittent and Continuous

Sibutramine


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-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

0 4 8 12 18 24 30 36 42 48

Weeks

Changein

BodyWeigh

t(kg)

Placebo

Intermittent

Continuous

Run-In Randomized Treatment (N=1001)

Wirth & Krause JAMA 2001; JAMA 286(11): 1331-9.

40


f W i ht L D ?


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Use drugs intermittently or for short intervals

Use combinations of drugs

Establish that weight loss continues

Select drugs that cause weight loss whentreating overweight patients for conditions

other than obesity

Only treat patients who respond

41

Combination of Pramlintide and

Ph t i B d W i ht


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0 10 20 30-15

-10

-5

0

Placebo

Pramlintide

Pram + Phen

Weeks of Treatment

WeightLoss(kg

)

Phentermine on Body Weight

Aronne L et al Obesity 2010;18:1739-174642


f W i ht L D ?


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other than obesity


43

Fluoxetine Fails to Maintain Body

W i ht L


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Weight Loss

0 10 20 30 40 50 60-6

-4

-2

0

Placebo

Fluoxetine

Weeks

We

igh

tLoss(k

g)

Goldstein et al IJO 1993;17:129-13544


f W i ht L D ?


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other than obesity


45

Metformin Treats Diabetes and

Lowers Weight Over 10 Years


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0 2 4 6 8 10

-6

-4

-2

0

2

4 PlaceboNever Adherent50% AdherentHighly Adherent

Time since Randomization

W

eightC

hange(%)

Placebo discontinued afteran average of 3.2 years

DPPOS: Diabetes Care 2012:April with approval46


f W i ht L D ?


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other than obesity


47

Variability of Response to

Th i L k AHEAD St d


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Months of Treatment

Weigh

tLoss(%

)

0 2 4 6 8 10 12 14-20

-15

-10

-5

0

10th %25th %

50th %

75th %

90th %

Therapy in Look AHEAD Study

Espeland ME et al Ann Epidemiol 2009;701-710

Conclusions

E i ht i ht i d t l


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Excess weight, weight gain and central

adiposity increase many health risks

Weight loss improves the risk profile in almostall instances

Obesity can be seen in the mirror but high

cholesterol or blood pressure cant

Obesity is a stigmatized condition and patients

may inappropriately want to use weight loss

medications because they know they are fat

Medications augment the effect of lifestyle on

weight loss 49

Conclusions


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But, ALL drugs have risks AND

Not all patients respond equally to any givenmedication

Most benefits from medication for obesity are

achieved in 6 months

Lifestyle-placebo effects vary between trials,

weight loss from baseline might be a bettercriterion than weight loss below placebo to

evaluate response.

50

Conclusions

Therefore:


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Physicians prescribing anti-obesity drugs

should ascertain that patients are

responding adequately, and if not modifytreatment

Several strategies can be used to mitigatepotential risks, including intermittent

treatment, combination therapy, selecting

effective drugs and stopping treatment for

unresponsive patients

51


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