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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
7/28/2019 20120328 29 EMDAC B1 03 Guest CoreSlides
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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Cardiac Abnormalities in Obesity
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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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
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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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 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
Year since DPP Randomization
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
Year since DPP Randomization
ChangeinWeight(kg)
Placebo Metformin Lifestyle
0 1 2 3 4 5 6 7 8 9 10
-8
-6
-4
-2
0
2
A. All Participants
Year since DPP Randomization
ChangeinWeight(kg)
Placebo Metformin Lifestyle
All ages
Age 45-59
Age 25-44
Age
60
Placebo Metformin Lifestyle
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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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10-year Costs of Treatment and Outs
Medical Care in the DPP/DPPOS
Diabetes Care 35: 723-730, 2012
10-year Costs of Treatment and Outs
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10-year Costs of Treatment and Outs
Medical Care in the DPP/DPPOS
Diabetes Care 35: 723-730, 2012
10-year Costs of Treatment and Outs
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10-year Costs of Treatment and Outs
Medical Care in the DPP/DPPOS
Diabetes Care 35: 723-730, 2012
10-year Costs of Treatment and Outs
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10-year Costs of Treatment and Outs
Medical Care in the DPP/DPPOS
Diabetes Care 35: 723-730, 2012
10-year Costs of Treatment and Outs
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10-year Costs of Treatment and Outs
Medical Care in the DPP/DPPOS
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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Primary HypothesisPrimary Hypothesis
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
Composite #2Composite #2
AllAll--cause deathcause death
NonNon--fatal MIfatal MI
NonNon--fatal strokefatal stroke
Hospitalization forHospitalization foranginaangina
Composite #3Composite #3
AllAll--cause deathcause death NonNon--fatal MIfatal MI
NonNon--fatal strokefatal stroke
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
Primary HypothesisPrimary Hypothesis
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Primary HypothesisPrimary Hypothesis
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
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Repeated Measures Adjusted for Clinic and Baseline Level
Average effect across all visits: -
5.27, p
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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
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Repeated Measures Adjusting for Clinic and Baseline Level
Average effect across all visits: 10.78, p
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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
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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
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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
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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)
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(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
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Variables Associated with PercentVariables Associated with Percent
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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
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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
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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%
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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%
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Prevalence of Achieving ADA Goal for HbA1c < 7.0%
Year DSE ILI P-value
Baseline 45% 47% NS
Year 1 50% 72%
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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
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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
Look AHEAD Research Group. Arch Int Med 2010;170:1566-75
45
P l f A hi i ADA G l f BP
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Prevalence of Achieving ADA Goal for BP
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47
Average effect across all visits: 1.70, p
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( 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
Baseline 112.26 112.37 NS
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
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LDL Cholesterol (mg/dl) Change from Baseline
Repeated Measures Adjusting for Clinic, Baseline Level,
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p j g , ,
and Medication Use Average effect across all visits: 0.47, p = 0.42
DSE
(mg/dl)
ILI
(mg/dl)
P-value
Baseline 112.26 112.37 NS
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
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Prevalence of Achieving ADA Goal for LDL-C
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53
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54
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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
Look AHEAD Research Group. Arch Int Med 2010;170:1566-75
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
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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
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Disclosures
Consultant to Takeda Global
Development
Nutrition Advisory Board for Herbalife
Advisor to Buckapound
2
Structure of My Presentation
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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
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Mortality and Morbidity
4
Risk Increases as BMI Rises
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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
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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
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Phlebitisvenous stasis
Coronary heart disease
Pulmonary diseaseabnormal function
obstructive sleep apnea
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
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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
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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
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& Risk of Cancer and Diabetes
10
Surgical Weight Loss Reduces
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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)
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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
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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
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Benefits of Weight Loss
14
Scoring for Change in MobilityStage
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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
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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)
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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
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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
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Orlistat Enhances Weight LossAbove Lifestyle/Placebo
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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
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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
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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
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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
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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
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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
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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
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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
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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
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-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
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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
How Can We Mitigate the Risk
f W i ht 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 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
How Can We Mitigate the Risk
f W i ht 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 whentreating overweight patients for conditions
other than obesity
Only treat patients who respond
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
How Can We Mitigate the Risk
f W i ht 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 whentreating overweight patients for conditions
other than obesity
Only treat patients who respond
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
How Can We Mitigate the Risk
f W i ht 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 whentreating overweight patients for conditions
other than obesity
Only treat patients who respond
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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