29 EMDAC B1 03 Guest CoreSlides

Pathophysiology of Obesity and CVD
Endocrine and Metabolism Drug Advisory Committee 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 Atherosclerosis University of Colorado Anschutz Medical Campus
CVD Mortality and Obesity:

Cancer Prevention Study II
Relative Risk of Death 3.0 2.6 2.2 1.8 1.4 1.0 0.6 <18.5
2
Men (n=84,376) Women (n=217,857) Non-smokers Without known heart disease
28 30 22 25 Body Mass Index (BMI)
35
Calle EE et al. NEJM 341:1097,1999
Metabolic Pathophysiology of Obesity and CVD

Hypertension Dyslipidemia Inflammation Diabetes
3
The Role of Adipose Tissue and Adipose Tissue Distribution and

the Metabolic Syndrome
Visceral vs. Subcutaneous Adipose Tissue

Adipose Tissue Function
Insulin action Catecholamine action Leptin PAI-1 Angiotensinogen IL-6 (cytokines) Adiponectin
6
Visceral vs. Subcutaneous

Subcutaneous Visceral Subcutaneous Visceral/Subcutaneous Visceral Visceral Subcutaneous
Visceral Adiposity: The Critical Adipose Depot
Subcutaneous Fat Abdominal Muscle Layer Intra-abdominal Fat
Abdominal Obesity and Coronary Heart Disease in Women: The Nurses Health Study
Incidence rate per 100,000 person-years
128 110
140 120 100 80 60 40 20 0 High (25.2 - <48.8) Middle (22.2 - <25.2) Low (12.2 - <22.2)
Follow-up of 8 years
83
106 89 77 46 55
97
Waist Girth Tertiles (cm)

High (81.8 - <139.7) Middle (73.7 - <81.8) Low (38.1 - <73.7)
Body Mass Index Tertiles (kg/m2)

Adapted from Rexrode KM et al. JAMA 280: 1843, 1998
Relationship Between Visceral Adipose Tissue and Insulin Action

Glucose disposal (mg/kg LBM/min)
18 16 14 12 10 8 6 4 2 0 0 1,000 2,000 3,000 4,000 5,000 Women Men
Visceral adipose tissue volume per unit surface area (mL/m2)

9
Banerji et al. Am J Physiol 1997; 273: E425E432
Pathogenesis: -Cell Compensation and Decompensation and T2DM

500
Insulin Secretion (U/mL)
-Cell Failure
400
300
Normal Glucose Tolerance Impaired Glucose Tolerance Type 2 Diabetes

0 1 2 3 4 5
200
100
Insulin Action (mg/kg EMBS per minute)
Insulin Resistance
10
Weyer C et al. J Clin Invest 104: 787, 1999
Hypertension Insulin Resistance Metabolism

C-II C-III B-100
TG
and
HDL cholesterol small dense LDL
VLDL
FFA
Insulin
IL-6
SNS
{
CRP
FFA
Fibrinogen
PAI-1
Prothrombotic State
11
{
-
Glucose TNF- IL-6
Insulin Glycogen
FFA
CO2
Adiponectin Triglyceride (intramuscular droplet)
Eckel RH et al, Lancet 365:1415, 2005
The Link Between Insulin Resistance and Endothelial Dysfunction

Lipolytically Active Abdominal Adipose Tissue
IL-1, IL-6, TNF
Vascular Endothelium
Vasodilation Shear Stress Inflammation Atherosclerosis Thrombosis CRP PAI-1

12
Steinberg HO, Baron AD. Diabetologia. 2002;45:623-634. Caballero AE. Obesity Res. 2003;11:1278-1289.
Pathogenesis of Hypertriglyceridemia in The Metabolic Syndrome production of atherogenic apo B-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
apo C-III VLD L
VLDL
TG
LPL
apo C-III TG Storage apo B-100 TG Synthesis SREBP-1c FFA
Hypertriglyceridemia
Obesity
Insulin Resistance FFA
Eckel RH, ATVB, 31:1946, 2011
Fat
Mass
Pathogenesis of Decreased HDL Cholesterol in The Metabolic Syndrome

cholesterol content of HDL
TG CETP
LPL
production of HDL2
HDL3 clearance
15
Inflammatory Markers and Insulin Resistance
15
Yudkin, JS et al, ATVB 19:976, 2001
CRP by Number of Metabolic Disorders (Dyslipidemia, Upper Body Adiposity, Insulin Resistance, Hypertension)
Mean Value of Log CRP 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 4 Number of Metabolic Disorders
16
Festa et al. Circulation 102:42-7, 2000
More Metabolic Syndrome

Other associated conditions
uric acid and gout Cognitive dysfunction Polycystic ovarian syndrome Non-alcoholic fatty liver disease Obstructive sleep apnea
17
19
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
20
Arrhythmias, prolonged QTc, sudden death
21 20
Cardiovascular Adaptations in Obesity

Interstitial fluid Vasodilatation
peripheral resistance
Left ventricular end diastolic pressure Heart rate Cardiac output

22
Poirier P and Eckel RH: The Heart and Obesity, Chpt 83, 2000, In: Hurst's The Heart

Coronary heart disease
23
Hazard Ratio for the Risk of Diabetes Over 17 Years in Healthy Young Adults, According to BMI in Adolescence and in Adulthood
37,674 young men, Staff Periodic Exam, Israeli Army Medical Corps
24
Tirosh A et al. NEJM 364:1315, 2011
Hazard Ratio for the Risk of Coronary Heart Disease Over 17 Years in Healthy Young Adults, According to BMI in Adolescence and in Adulthood
37,674 young men, Staff Periodic Exam, Israeli Army Medical Corps
25
Tirosh A et al. NEJM 364:1315, 2011


Deep venous thrombosis
26
Myocardial Response to ObesIty and Insulin Resistance

Cardiac myocyte hypertrophy Autonomic neuropathy
Insulin-like growth factor-1
Myocardial ischemia
Microangiopathy Endothelial dysfunction
Parasympathetic Sympathetic
Metabolic factors
Dysglycemia Intracellular triglyceride accumulation
Reduced cardiac function

Impairment in myocyte calcium transport Alteration in contractile proteins Interstitial fibrosis
Myocardial inflammation
Oxidative stress AGEs Mitochondrial dysfunction Apoptosis
Cardiac arrhythmias
27
Prolonged action potential Electrical remodeling
Hypertension and Obesity: NHANES III (1988-1994)
Brown CD et al, Obes Res 8:605, 2000
Mechanisms Relating Obesity to Hypertension
Narkiewicz K et al Obes Rev 7:155, 2006
Duration of Severe Obesity: Systolic Blood Pressure

Systolic blood pressure (mmHG)
140 135 130 125 120 115 110 0

5 10 15 20 25 30
years
30
Alpert MA et al. Am J Card 76:1194, 1995
Duration of Severe Obesity: LV End Diastolic Dimension

LV dimension diastole (mm)
7 6.5 6 5.5 5 4.5 4 0

5 10 15 20 25 30
years
31
Alpert MA et al. Am J Card 76:1194, 1995
CVD Mortality, Hypertension in the Womens Health Initiative
32
Oparil S, Card Rev 14:267, 2006
Contributors to Hypertension in the Womens Health Initiative
33
Oparil S, Card Rev 14:267, 2006


Deep venous thrombosis
Autonomic dysfunction
34
Arrhythmias, prolonged QTc, sudden death
ECG Changes Found in Obesity

Clinically significant

35
Heart rate QRS interval QTc interval False positive criteria for inferior myocardial infarction 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, 2007
Less clinically significant
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

36
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, 2006
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, 2007
37
Changes in Cardiac Geometry and Function Two Years after Bariatric Surgery
38
Owan T et al, JACC 57:732, 2011
Effect of Bariatric Surgery on Physical and ECG Parameters

Pre surgery Age (year) Weight
(kg)
Post surgery
Pre surgery
Post surgery
Men (n=32)
Women (n=68)
4011 173.141. 103.921. <0.0001 2 1 57.013.6 8315 9712 42826 36828 34.46.5 6211 9910 41118 41033
<0.0001 <0.0001 0.36 0.01 <0.0001
439 131.023. 4 50.48.4 7913 8710 43021 37826
0.12
83.415. <0.0001 4 32.36.0 <0.0001 628 9010 41025 41518

<0.0001 0.15 <0.0001 <0.0001
BMI
(kg/m2)
Heart rate (bpm) QRS (ms) QTc (ms) QT (ms)

39
Gilbert P et al, unpublished
Conclusions
Obesity confers an increased risk for CVD. Insulin resistance is a major contributor to the 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 comorbidities.
40
Thank You!
Obesity and Type 2 Diabetes

Meeting on Obesity Drugs Endocrinologic and Metabolic Drugs Advisory Committee March 28, 2012 William C. Knowler, MD, DrPH
National Institute of Diabetes and Digestive and Kidney Diseases Phoenix AZ, USA
80 C a s e s /1 0 0 0 p e rs o n -y r 60 40 20 0
Incidence of Diabetes by BMI in Adult Pima Indians
<20
Knowler: Am J Epidem, 1981
-25
-30
-35
-40
40
2
Body Mass Index (kg/m2)
Diabetes Prevention Program (DPP)

Multicenter randomized clinical trial in U.S.A. Hypothesis: Type 2 diabetes can be prevented or delayed by treating modifiable risk factors Persons at high risk of type 2 diabetes 1996 2001 with long-term follow-up to 2014
NEJM 346: 393-403, 2002
Diabetes Prevention Program (DPP) Eligibility and Outcome

Age > 25 years Plasma glucose
Fasting 5.3- <7.0 mmol/l (95-125 mg/dl) and 2 hour 7.8- <11.1 mmol/l (140-199 mg/dl)
Body mass index > 24 kg/m2 Primary outcome: diabetes by FPG (6 mo.) or OGTT (annual)
NEJM 346: 393-403, 2002
4
Diabetes Prevention Program

Eligible participants Randomized
Placebo n = 1082
Metformin n = 1073
Lifestyle (ILS) n = 1079
NEJM 346: 393-403, 2002
Total n = 3,234
Mean Weight Change in the DPP

Placebo Metformin Lifestyle
NEJM 346: 393-403, 2002
Percent developing diabetes DPP Incidence of Diabetes All Placebo (n=1082)

40
participants
Cumulative incidence (%)
Metformin (n=1073, p<0.001 vs. Placebo) Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac ) Lifestyle (n=1079, vs. Plac) Metformin, Metformin (n=1073, p<0.001 p<0.001 vs. Placebo (n=1082) p<0.001 vs. Placebo)
30
20
Risk reduction 31% by metformin 58% by lifestyle
10
0 0 1 2 3 4
Years from randomization

NEJM 346: 393-403, 2002
7
Diabetes Incidence Rates in DPP

12 Cases/100 person-yr
31%
58%
11.0
0
PLAC
7.8
MET
4.8
ILS
8
NEJM 346:393-403, 2002
Diabetes Incidence Rates by Ethnicity

Lifestyle
Cases/100 person-yr
12
Metformin
Placebo
0 White (n=1768) African American (n=645) Hispanic (n=508) American Indian (n=171) Asian (n=142)
9
The DPP Research Group, NEJM 346:393-403, 2002
Keys to DPP Lifestyle Success

Weight loss was the key to diabetes prevention Reduction of total calories, especially fat calories Achieving 150 minutes of activity each week
10
DPP: Hazard Rate for Developing Diabetes As A Function of Weight Change From Baseline
20
Intensive Lifestyle Group
Hazard rate per 100/yr
10
15
Average Risk
0
-15
-10
-5
+5
Mean weight change from baseline (kg)

Diabetes Care 29: 2102-2107, 2006
11
Diabetes Risk by Weight Change in the DPP

Diabetes incidence / 100 pers-yr Weight loss explained 64% of the risk reduction from metformin (a weight loss drug).
16
placebo
11
metformin
6
-10 -8 -6 -4 -2 0 2 4 Change from baseline weight (kg) 6
12
Diabetes 56: 1153-59, 2007
TCF7L2 Genotype and Diabetes Incidence in the DPP

C ases/100 p erso n -yr 20 15 10 5 0 Placebo
DPP Research Group: NEJM 2006
Genotype at rs7903146 (n=3,537)
CC
49%
CT
41%
TT
9%
Metformin
Lifestyle
13
Other Benefits of DPP Lifestyle Intervention on CVD Risk Factors

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 effect
Diabetes Care 2005; Diabetes 2005; Ann Internal Med 2005
14
DPP Outcomes Study (DPPOS) 2002 2014

Masked phase ended, metformin continued, placebo discontinued, all offered lifestyle.
Long-term effects of DPP interventions on

Weight loss maintenance Further diabetes incidence Diabetes complications and death
Lancet 374:1677-1686, 2009
15
10-Year Weight Change: DPP + DPPOS
Lancet 374:1677-1686, 2009
16
Cumulative Incidence of Diabetes
Lancet 374:1677-1686, 2009
17
Mean Weight Changes (kg) Since Randomization by Age

Placebo
A. All Participants
Metformin
C. Age Group 25 - 44 y
Lifestyle
Placebo Metformin Lifestyle
Placebo
2
Metformin
Lifestyle
2
Change in Weight (kg) -4 -2
All ages
Age 25-44
-6
-8
4 5 6 Year since DPP Randomization
10
-8 0
-6
4 5 6 Year since DPP Randomization
10
E. Age Group: 45 - 59 y
G. Age Group: 60 y
Placebo
2
Metformin
Lifestyle
2
Placebo
Metformin
Lifestyle
-6
Age 45-59
-8 -8 0 1 2 3 4 5 6 Year since DPP Randomization 7 8 9 10 0 1 2 3
-6
Age 60
4 5 6 Year since DPP Randomization 7 8 9 10
18
Micro- and MacroVascular Outcomes in the DPPOS?

Expected in 2014
19
10-year Costs of Treatment and Outside Medical Care in the DPP/DPPOS
Diabetes Care 35: 723-730, 2012
20
Diabetes Care 35: 723-730, 2012
21
Diabetes Care 35: 723-730, 2012
22
Diabetes Care 35: 723-730, 2012
23
Diabetes Care 35: 723-730, 2012
24
Weight Loss with Lifestyle Counseling and Placebo or Orlistat (XENDOS)

3,277 obese nondiabetic adults
0 W eig h t lo ss (kg ) -3 -6 -9 -12
0 1 2 3 4
Placebo (34% compl.)
Orlistat (52% compl.)
Years from Randomization

Torgerson JS: Diab. Care, 2004
25
Diabetes Incidence with Lifestyle Counseling and Placebo or Orlistat in IGT (XENDOS)
C u m u lative In cid en ce (% ) Placebo (34% compl.) 10 8 6 4 2 0
0 1 2 3 4
Orlistat (52% compl.)
Cannot interpret because most dropped out. HRR = 0.63

(95%CI = 0.46 0.86) p<0.01
Years from Randomization

Torgerson JS: Diab. Care, 2004
26
Prevention or Delay of Type 2 Diabetes with Drugs or Lifestyle Intervention

Several other clinical trials with similar results Little evidence for long-term non-glycemic outcomes
27
Early Life Predictors of Obesity and Diabetes:

The Pima Indian Longitudinal Study
28
Relative Body Weight in Children by Maternal Diabetes

Mean % Desirable Weight
Mother During Pregnancy
150 140 130 120 110 100 Birth
Diabetic Prediabetic Nondiabetic
5-9
10-14
15-19
29
Pettitt: NEJM 1983
Age (years)
Diabetes in Offspring By Maternal Diabetes in Pregnancy

P revalen ce (% ) 60 40 20 0 5-9 10-14 15-19 Age (years)
30
Mother during pregnancy
nondiabetic prediabetic diabetic
20-24
25-29
Updated from Pettitt: Diabetes, 1988
10-Year Diabetes Incidence by Relative Weight, Fasting Insulin, and 2-hr Glucose in 15-19 Year-old Pima Indians with > 1 Diabetic Parent*
25 Incidence (%) 20 15 10 5 0 Relative Weight
McCance: Diabetologia, 1994
low
Tertile Groups
middle
high
Fasting Insulin
2-h Glucose
31
* Incidence = zero if both parents nondiabetic.
Diabetes in Pregnancy and Offspring: The Vicious Cycle

Pregnant Woman with Diabetes
Young Woman with Diabetes

Pettitt & Knowler, J Obes Wt Reg 1988
Infant (daughter) of Diabetic Mother

32
Conclusions
Overweight / obesity strongly related to type 2 diabetes Metformin & lifestyle interventions in adults can reduce
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 or without drugs), but maintenance is difficult
33
There are many ways to treat obesity
If many cures are offered for an illness, you may be sure that the illness has no cure.
Anton Chekhov: The Cherry Orchard, 1904
34
Look AHEAD (Action for Health in Diabetes) Trial

Rena R. Wing, Ph.D.
Professor of Psychiatry & Human Behavior Warren Alpert Medical School of Brown University Director, Weight Control & Diabetes Research Center The Miriam Hospital Providence, Rhode Island
Overview
Rationale and design Year 4 results: changes in weight and fitness Year 4 results: changes in cardiovascular disease (CVD) risk factors
A multicenter, randomized clinical trial examining the long-term effects (up to 13.5 years) of an intensive lifestyle intervention program on cardiovascular morbidity and mortality in overweight or obese persons with Type 2 Diabetes.
Funding Sources
National Institute of Diabetes and Digestive and Kidney Diseases National Heart, Lung, and Blood Institute National Institute of Nursing Research National Center on Minority Healthy and Health Disparities Office of Research on Women's Health Centers for Disease Control and Prevention
5
Benefits of Weight Loss

Weight loss is strongly recommended for overweight patients with Type 2 diabetes Short term (< 1yr) studies show benefits of weight loss for
Lipids Blood pressure Insulin sensitivity Glycemic control
Lack of Data on Long Term Benefits
No randomized trials have been conducted to determine long term consequences of intentional weight loss Surgical studies suggest positive effects of large weight losses However, some observational studies suggest that weight loss or weight cycling is associated with increased morbidity/mortality
Look AHEAD is a multicenter RCT examining the long-term effects (up to 13.5 years) of an intensive lifestyle intervention program to produce weight loss and increase physical activity on cardiovascular morbidity and mortality in over 5,000 overweight or obese persons with type 2 diabetes.
8
Randomized Study Arms

Intensive lifestyle intervention (ILI) Diabetes support and education (DSE) (usual care control group)
Primary Hypothesis
The ILI, as compared to DSE, will reduce the incidence rate of an aggregate endpoint of CVD defined 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
Secondary Outcomes
Composite #1

Composite #3

CVD death Non-fatal MI Non-fatal stroke
Composite #2

All-cause death Non-fatal MI Non-fatal stroke Hospitalization for angina
All-cause death Non-fatal MI Non-fatal stroke Hospitalization for angina Hospitalization for CHF Coronary artery bypass grafting (CABG) or angioplasty Carotid endarterectomy Peripheral vascular disease
11
Other Outcomes
Cardiovascular disease risk factors Diabetes control and complications General health Hospitalizations Quality of life and psychological outcomes Costs and cost effectiveness
12
Eligibility Criteria
Type 2 diabetes Overweight (BMI > 25 kg/m2 or > 27 kg/m2 if on insulin) Age 45-75 years > 33% minorities With or without history of CVD BP < 160/100 mmHg HbA1c < 11% Triglycerides < 600 mg/dl < 30% using insulin
13
Baseline Characteristics of Participants Lifestyle (N=2570) 59% 37% 58.6 15% 35.9 100.6 113.8 15% DSE (N=2575) 60% 37% 58.9 16% 36.0 100.9 114.1 14%
14
Women Minority Age (years) Insulin Users Baseline BMI Baseline Weight (kg) Baseline Waist (cm) History of Prior CVD Event
Intensive Lifestyle Intervention

Weekly for 6 months 3x per month for 6 months 2x per month from year 2 to end Group plus individual sessions Diet , physical activity, and behavioral strategies
15 Look AHEAD Research Group. Diabetes Care, 2007;30:1374-83.
Recommendations
Weight Loss Lose 10% of body weight and maintain Dietary Intake 1200-1500 kcal/day < 250 lb 1500-1800 kcal/day > 250 lb < 30% calories from fat Meal replacements and menu plans Physical Activity Gradual increases in brisk walking 175 min/wk 10,000 steps per day
16
Diabetes Support and Education (DSE)

3-4 meetings / year To promote retention Health education topics Diet Exercise Social Support
17
Medication Adjustments
Made by participant's own physician Study protocol for adjusting diabetes medications during initial weeks of intervention
18
Study Design
90% power to detect an 18% reduction in CVD events over 10.5 years of follow-up Assumed 3.125% CVD event rate in control Actual 0.7% CVD event rate in control at 3 years Convened Endpoint Working Group (masked to study results)
19
Why Low Event Rate?

Secular trends Trial participants healthier then cohort studies Graded exercise test
20
Changes to Study Design

Extended study duration by 2 years (11.5 to 13.5 years) Broadened definition of primary endpoint to include hospitalized angina
Brancati, et al. Clinical Trials, 2012, 9; 113-124
21
Primary Hypothesis
The ILI, as compared to DSE, will reduce the incidence rate of an aggregate endpoint of CVD defined 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.
22
Year 4 Results: Changes in Weight and Fitness
23
Year 4 Retention
DSE
Randomized, N Seen Year 4* % of randomized % of current cohort 2,575 2,403 (93.3%) (95.8%)
ILI
2,570 2,420 (94.2%) (96.5%)
*Outcomes assessment and/or weight measurement

24
Percent Weight Change from Baseline

Repeated Measures Adjusted for Clinic and Baseline Level Average effect across all visits: - 5.27, p<0.001
% Weight change from baseline
0 -1 -2 -3 -4 -5 -6 -7 -8 -9 0 1 2
Year
DSE Baseline (kg) Y1 BL Y2 BL

DSE ILI
3 4
ILI 100.6 - 8.50 - 6.35 - 5.04 - 4.66
P-value NS <.0001 <.0001 <.0001 <.0001
100.8 - 0.63 - 0.93 - 0.92 - 1.01
Y3 BL Y4 BL
Percentage of Participants in ILI and DSE Who Met Different Weight Loss Criteria at Year 4
DSE Any weight loss (vs. gain) 5% weight loss 10% weight loss 55% 25% 10%
ILI 74% 46% 23%
26
Percent Fitness Change from Baseline

Repeated Measures Adjusting for Clinic and Baseline Level Average effect across all visits: 10.78, p<0.001
% Fitness change from baseline
30 DSE 20 10 0 -10 0 1 2 Year 3 4 ILI

DSE Baseline Y1 BL Y4 BL 5.20 5.05 - 0.96 ILI 5.23 20.41 5.18 Pvalue NS <.0001 <.0001
Gender and Insulin Use Do Not Affect Year 4 Weight Loss

Percent weight loss NS Percent weight loss
NS
28
4-Year Weight Loss Outcomes

0 -1 -2 -3 -4 -5 -6 Overweight Class I Class II Severe
Change in body weight (%)
* Overweight significantly different from all other groups (p<0.001)

29
By Year 4, No Significant Differences in Weight Losses across Race/Ethnicity Groups

% Reduction in Initial Weight
0 2 4 6 8 10 12 0 1 2 3
American Indian/ Other African American Hispanic Non-Hispanic White
4
30
Year
Oldest Participants Lost Significantly More than Younger Participants at all Assessments
% Reduction in Initial Weight
0 2 4 6 8 10 0 1 2 3 4
31
45-54 yr 55-64 yr 65-76 yr
Year
Success of Those Aged 65 74 is Related to Better Adherence

Treatment Contact in Year 1 Age 45 54 55 64 65 74 35 35 37 18 21 22 1179 1247 1337 1695 1621 1465 Treatment Contact in Years 2 4 Activity (kcal/week) Year 4 Calorie Intake Year 4
32
Four-Year Weight Loss Trajectories of 887 ILI Participants Who Had Lost 10% Initial Weight at Year 1 +4 +2 0 2
4 N=88 (9.9%)
Gained 0-5%
Percentage Weight Loss
N=174 (19.6%) N=99 (11.2%) N=152 (17.1%)
6 8 10 12 14 16 18
5-6.9% 710% 10%
N=374 (42.2%)
2
Years
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)
25
p < .0001
p < .0001
Treatment Sessions
20 15
23.6 22.7 18.5 16.8
10 5 0 10% 5 - 9.9% 0 - 4.9% Gained

34
Weight Change at Year 4
Mean Annual Number of Meal Replacements Used in Years 2-4 for

140 120
Mean Weekly Kcal Expenditure at Year 4 (as Determined by Paffenbarger)
p < .02
p < .05
2500 2000
Meal Replacements
Kcal/wk of Activity
100 80 60 40 20 0
p < 0.005 for all comparisons with > 10% group
1500 1000
125.7
103.2
80.8
84.2
1997.9
500 0
1406.2
1127.3
949.3
> 10%
5 - 9.9%
0 - 4.9%
Gained
> 10%
5 - 9.9%
0 - 4.9%
Gained
Weight Change- Year 4
Weight Change- Year 4
35
Variables Associated with Percent Weight Losses at Year 4

Variable Variance Explained 2.59% 4.0% 1.7 1.8% 21.9%
Baseline weight, gender, age, ethnicity, insulin Treatment attendance Dietary intake or physical activity Year 1 weight loss
36
Conclusions : Changes in Weight and Fitness

ILI produced significantly greater changes in weight and fitness than DSE through 4 years Nearly 50% of ILI participants have maintained a loss 5% of initial weight at year 4. The intervention produced clinically significant weight loss in all subsets of a demographically and ethnically diverse population. The best predictors of long-term weight loss were:

Adherence to diet and exercise recommendations Initial weight loss
37
Look AHEAD Research Group. Arch Int Med 2010;170:1566-75
Year 4 Results: Changes in CVD Risk Factors
38
HbA1c Change from Baseline

Repeated Measures Adjusting for Clinic and Baseline Level Average effect across all visits: -0.27, p<0.001
A1c change from baseline
0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8 0 1 2

Year
DSE Baseline Y1 BL Y2 BL Y3 BL
DSE ILI 3 4
ILI 7.25 - 0.64 - 0.37 - 0.26 - 0.19
P-value NS <.0001 <.0001 <.0001 0.0014
7.31 - 0.12 - 0.08 - 0.09 - 0.07
Y4 BL
Use of Any Diabetes Drug

Year No Baseline Use Baseline Use
DSE N=348 1 2 3 4 33% 46% 58% 66%
ILI N=354 10% 17% 27% 40%
p-value <.0001 <.0001 <.0001 <.0001
DSE N=2208 97% 96% 95% 96%
ILI N=2202 89% 88% 89% 91%
p-value <.0001 <.0001 <.0001 <.0001
40
Use of Any Insulin

No Baseline Use Year DSE N=2167 1 2 3 4 4% 7% 9% 12% ILI N=2190 2% 3% 4% 7% p-value <.0001 <.0001 <.0001 <.0001 DSE N=408 92% 86% 86% 88% ILI N=380 81% 76% 78% 77% p-value <.0001 0.0004 0.0037 0.0004 Baseline Use
Prevalence of Achieving ADA Goal for HbA1c < 7.0% Year Baseline Year 1 Year 2 Year 3 Year 4 DSE 45% 50% 51% 51% 51% ILI 47% 72% 63% 60% 57% P-value NS <.0001 <.0001 <.0001 <.0001
42
SBP (mmHg) Change from Baseline

Repeated Measures Adjusting for Clinic and Baseline Level Average effect across all visits: -2.36, p<0.001
SBP change from baseline (mmHg)
0 -1 -2 -3 -4 -5 -6 -7 -8 -9 0 1 2
Year
DSE (mmHg) Baseline Y1 BL Y2 BL

DSE ILI 3 4
ILI (mmHg) 128.22 - 7.03 - 4.96 - 4.70 - 4.62
P-value NS <.0001 <.0001 0.0009 0.0101
129.49 - 2.32 - 3.06 - 3.12 - 3.37
Y3 BL Y4 BL
43
DBP (mmHg) Change from Baseline

Repeated Measures Adjusting for Clinic and Baseline Level Average effect across all visits:-0.43, p=0.01
DBP change from baseline (mmHg)
0 DSE -1 ILI
DSE (mmHg) Baseline 70.37 - 1.64 - 2.18 - 2.71 - 3.41 Y1 BL Y2 BL Y3 BL Y4 BL
ILI (mmHg) 69.93 - 3.07 - 2.69 - 2.76 - 3.16
Pvalue NS <.0001 0.0275 0.8305 0.2868
-2
-3
-4 0 1 2 Year 3 4
Use of Any Antihypertensive Drug

Year No Baseline Use
DSE N=684 1 2 3 4 22% 32% 40% 47% ILI N=661 16% 25% 33% 43%
Baseline Use
DSE N=1872 95% 96% 95% 95% ILI N=1895 94% 94% 94% 94%
p-value 0.01 0.005 0.01 0.17
p-value 0.43 0.002 0.23 0.58

45
Prevalence of Achieving ADA Goal for BP <130/80 mmHg Year Baseline Year 1 Year 2 Year 3 Year 4 DSE 50% 57% 60% 60% 61% ILI 54% 69% 64% 63% 63% P-value NS <.0001 0.0033 0.0490 0.0904
46
HDL Cholesterol (mg/dl) Change from Baseline

Repeated Measures Adjusting for Clinic and Baseline Level Average effect across all visits: 1.70, p<.001
HDL change from baseline (mg/dl)
5 4 3 2 1 0 0 1 2 Year 3 4
DSE (mg/dl) Baseline Y1 BL Y2 BL

DSE ILI
ILI (mg/dl) 43.48 3.37 3.78 3.58 3.95
P-value NS <.0001 <.0001 <.0001 <.0001
43.48 1.35 1.93 2.04 2.58
Y3 BL Y4 BL
47
LDL Cholesterol (mg/dl) Change from Baseline

Repeated Measures Adjusting for Clinic and Baseline Level Average effect across all visits: 1.57, p=0.009
LDL change from baseline (mg/dl)
0 DSE ILI -10
DSE (mg/dl) Baseline Y1 BL 112.26 - 5.50 - 11.10 - 16.00 - 18.75
ILI (mg/dl) 112.37 - 5.11 - 9.43 - 13.88 - 16.64
P-value NS 0.60 0.05 0.01 0.01
-20
Y2 BL Y3 BL
-30 0 1 2 Year 3 4
Y4 BL
48
Use of Lipid Lowering Medications

No Baseline Use Year DSE N=1313 1 2 3 4 25% 40% 47% 53% ILI N=1310 18% 29% 39% 47% p-value <.0001 <.0001 <.0001 0.005 DSE N=1243 92% 91% 89% 91% ILI N=1246 90% 89% 90% 90% p-value 0.08 0.56 0.27 0.53 Baseline Use
49
LDL Cholesterol (mg/dl) Change from Baseline Repeated Measures Adjusting for Clinic, Baseline Level, and Medication Use
Average
effect across all visits: 0.47, p = 0.42
LDL change from baseline (mg/dl)
0 -2 -4 -6 -8 -10 -12 -14 -16 0 1 2

Year
DSE ILI
DSE (mg/dl) Baseline Y1 BL Y2 BL Y3 BL Y4 BL 112.26 - 3.70 - 7.62 - 12.02 - 13.52
ILI (mg/dl) 112.37 - 4.44 - 7.47 - 10.64 - 12.45
P-value NS 0.33 0.85 0.08 0.19
50
Prevalence of Achieving ADA Goal for LDL-C <100 mg/dl

Year Baseline Year 1 Year 2 Year 3 Year 4 DSE 37% 45% 53% 60% 65% ILI 37% 44% 51% 58% 61% P-value NS 0.36 0.37 0.07 0.02
51
Weight Loss of 5 10 % produces significant improvements in CVD risk factors at year 1 (except LDL-C)
52
53
54
55
Conclusions : Changes in CVD Risk Factors

ILI has produced sustained improvements in glycemic control, SBP, and HDL-C as compared to DSE. LDL-C improved more in DSE than in ILI due to increased statin use; after adjusting for medications, changes in LDL-C did not differ significantly between groups Modest weight losses improved CVD risk factors, with the exception of LDL-C
56
Implications for FDA

Intensive lifestyle interventions can produce sustained benefits for weight and fitness across diverse age, gender, ethnic/racial groups and weight categories Initial weight loss and adherence are the strongest predictors of long term weight loss Modest weight losses can produce sustained improvements in glycemic control, SBP, and HDL-C Look AHEAD will continue to follow participants to determine the long-term impact of intensive lifestyle intervention on CVD morbidity and mortality
57
Percentage of Participants in ILI and DSE Groups Who Met Different Weight Loss Criteria at Year 4
100 90 80 % of Participants 70 60 50 40 30 20 10 0 5% 0% Weight Gain >0 % 5% 7 % Weight Loss 10 % 15 %
58
Look AHEAD Research Group, 2011
Intensive Lifestyle Intervention (ILI) Diabetes Support & Education (DSE)

74%
55% 45% 46% 35% 26% 18% 8% 25% 18% 23% 10% 9% 4%
Food and Drug Administration Washington DC March 28-29, 2012
Drugs to Treat Obesity:

Cardiovascular and Other Risks
George A. Bray, MD, MACP, MACE Boyd Professor Pennington Center Baton Rouge, LA
1
Disclosures
Consultant to Takeda Global Development Nutrition Advisory Board for Herbalife Advisor to Buckapound
Structure of My Presentation
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 Mortality and Morbidity
Risk Increases as BMI Rises

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.
64
Yearly Deaths per 1000 (99% CI)
32
Male
16
Female
8 15 20 25 30 35 40
5
45
Body Whitlock G Prospective Studies Collaboration Lancet. 2009 Mar 28;373(9669):1083-96.
Mass Index
Disease-Specific Increase in Mortality Rate per 5 BMI Units

Overall mortality Diabetes mellitus Hepatic disease Renal disease Vascular disease Malignancy 30% 116% 80% 60% 40% 10%
6
Whitlock G Prospective Studies Collaboration Lancet. 2009 Mar 28;373(9669):1083-96.
Medical Complications of Obesity

Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Gall bladder disease Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Osteoarthritis Skin Gout Phlebitis venous stasis
7
Idiopathic intracranial hypertension Stroke Cataracts Coronary heart disease Diabetes Dyslipidemia Hypertension Severe pancreatitis Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate
Risks Are Related to Fat Mass and Metabolic Effects of Obesity

Environment Activity Genes Food Intake
Excess fat stores Metabolic Diseases Weight-Related Diseases
Diabetes
NAFLD
CVD
Stigma Sleep apnea
Osteoarthritis
GB Disease
Cancer
Bray GA J Clin Endocrinol Metab. 2004 Jun;89(6):2583-9.
BMI Has Biggest Effect on Diabetes

Women
6 6
Men
Relative Risk
5 4 3 2 1 0 <21 22 23 24 25 26 27 28 29 30
Relative Risk
5 4 3 2 1 0 <21 22 23 24 25 26 27 28 29 30
BMI (kg/m2)
Type 2 diabetes Cholelithiasis
BMI, body mass index. Willett WC et al. N Engl J Med. 1999;341(6):427434.
BMI (kg/m2)
Hypertension 9 Coronary heart disease
Weight loss Benefits CVD Mortality, & Risk of Cancer and Diabetes
10
Surgical Weight Loss Reduces Mortality SOS Study

Cumulative Mortality (%)
14 12 10 8 6 4 2 0
Control
Surgery P=0.04
10
12
14
16
No. at Risk Surgery 2010 2001 1987 1821 1590 1260 760 Control 2037 2027 2016 1842 1455 1174 749 Sjostrom L, et al. N Engl J Med. 2007;357(8):741-752.
Years
422 422
169 156
11
Incidence of myocardial infarction (MI) in the SOS control and surgery group
Fatal MI
0.025 0.09 Control (37 events) Surgery (22 events) 0.020
Log-rank test P=0.039
Total MI Kaplan-Meier cumulative incidence

0.08 0.07 0.06 0.05 0.04 Control (136 events) Surgery (122 events)
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
Kaplan-Meier cumulative incidence
Unadj. HR=0.58 95% CI: 0.34-0.979
0.015
Adj HR=0.52 95% CI: 0.31-0.89 P=0.02
0.010
P=0.02
0.03 0.02 0.01 0.00
P=0.02
0.005
0.000 0
Number at risk Control 2037 Surgery 2010
8 10 12 14 16 18
8 10 12 14 16 18
Follow-up time, years

1993 1970 1423 1557 405 412
Follow-up time, years

Control 2037 Surgery 2010 1958 1943 1369 1502 384 390
12
Sjstrm L, et al: JAMA 2012; 307:56-65
Cardiometabolic Risk is Reduced

40 0
89 82 133 71 66 67 127 121 No. of subjects
50
25
HDL CHOL
Risk factor changes (%)
-40 -80
TG Insulin 0 5 40
-100-40 -30 -20 -15 -10 -5
-100 -100 -40 -30 -20 -15 -10 -5

5
40
15 0 -15
89 82 133 71 66 67 127 121 86 No. of subjects

0
No. of subjects
89 .
82 133 71
66
67 127 121 86
-5
Uric acid Glucose

-10
SBP DBP -100 -40 -30 -20 -15 -10 -5 0 5 40
-30 -100-40 -30 20 15 10 -5 0 5 40 Sjstrm CD et al. Obes Res. Body weight 1997;5:519-530.
changes (kg)
There Are Other Important Benefits of Weight Loss
14
Scoring for Change in Mobility

Stage 1
Vigorous Activity Walking- 1 mi Bending Moderate activity Climbing 1 flight Walking 1 block
1 0
1 0
1 0
15
Rejeski J et al NEJM 2012;March 29; with approval; on-line after 5 PM March 28 NEJM.org
Effect of Age and Weight Loss on Mobility

Diabetes Support and Education
1 1
Intensive Lifestyle Intervention Mobility Score

0.8 0.6 0.4 0.2 0 1 2 3 4
Mobility Score
0.8 0.6 0.4 0.2 0 1 2 3 4
Time
Time
Rejeski J et al NEJM 2012;March 29; with approval; on-line after 5 PM March 28 NEJM.org
Sleep Disordered Breathing in Obese Patients with Type 2 Diabetes (N=305)

22.6% Severe 13.4% No Obstructive Sleep Apnea
AHI < 5 AHI 5-14.9 AHI 15-29.9 AHI > 30
30.5% Moderate
Foster et al. Diabetes Care. 2009 Jun;32(6):1017-9.
33.5 % Mild
17
Changes in Weight and AHI over 4 yr

Change in Weight (Kg)
8 4 0 -4 -8 -12 0 1 2 Year 4
-- DSE -- ILI
Change in AHI
8 DSE 4
DSE
0 -4 ILI
ILI
-8 -12 0 1 2 Year 4
Why Do We Need Drugs to Treat Obesity?
19
Orlistat Enhances Weight Loss Above Lifestyle/Placebo

% Change in body weight (SE)
-0 -1 -2 -3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -10 0
SB Placebo tid Orlistat 120 mg tid
10
20
30
DB
40
50
60
70
80
DB
90 100 110
Week
Mildly hypocaloric diet
Weight maintenance (eucaloric diet)
Sjostrom, L et al Lancet, 1998;132:167-172
How Much Weight Loss Is Needed to Prevent Type 2 Diabetes?

20
Incidence Rate per 100 Person-Years
Preferred
Adequate
15
10
-10
-5
0 0
+5
Change in Weight From Baseline (kg)

Redrawn from: Hamman, et al Diabetes Care 29:2102-2107, 2006
21
Medications Produce More Weight Loss Than Lifestyle

0 Weight Loss (kg or %) -2 -4 -6 -8 Weighted Mean Differences: -3.01 (-402, -201) -2.98 (-3.92, -2.05) Orlistat + Placebo
22
-10 Treatment Control Lifestyle Lifestyle

Adapted from LeBlance et al Ann Int Med 2011;155:434-447
How Do Drugs Stack-Up?

Drug Phentermine Diethylpropion Mazindol Orlistat Fluoxetine Bupropion Pramlintide Exenatide Liraglutide Metformin # Studies 6 9 22 15 6 2 1 12 8 3 Length 13 wks 18 wks 11 wks > 1 yr 24 wks 24 wks 1 yr 24 wks 24 wks 1 yr Wt Loss -6.4 kg -6.5 kg -5.7 kg -5.3kg -4.8 kg -8.0 kg -9.0 kg -2.9 kg -2.8 kg -2.8 kg*
23
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 press
How Do Drugs Stack-Up?

Drug Sibutramine Rimonabant Lorcaserin Cetilistat Tesofensine Phen/Fenfluramine Phen/Topiramate Buprop/Naltrex Pram/Phentermine Pram/Leptin # Studies 10 4 2 1 1 1 2 2 1 1 Length > 1 yr > 1 yr 1 yr 12 wks 6 mos 34 wks > 1 yr > 1 yr 24 wks 24 wks Wt Loss -6.4 kg -6.3 kg -5.8 kg -4.1 kg -11.3 kg -14.2 kg -10.2 kg -8.7 kg -11.3 kg -11.5 kg
24
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 press
Surgery Is Superior to Medical Therapy for Weight Loss in Diabetes

Change in Hemoglobin A1c
10 9 8 7 6 5 0 3 6 9 12
Gastric Bypass M ed Therapy Sle eve
Change in Fasting Glucose

250
Fasting Glucose (mg/dl)
Hemoglobin A1c (%)
200 150 100

Sleeve M ed Therapy
50 0 0 3 6
Gastric Bypass
12
Months
Months
Change in Number of Anti-Diabetic Medicatios

4
Change in BMI
40
M ed Therapy
Number of Anti-diabetic Medications
M ed Therapy
3 2
Sleeve
BMI (kg/m2)
35 30 25 20
Sle eve
1
Gastric Bypass
Gastric Bypass
0 0 3 6 9 12
12
Months
Months
25
Schauer P. et al NEJM 2012; March 26
What Predicts Weight Loss?
Answer: Initial Weight loss
26
One Year Weight Loss Predicted by Initial Weight Loss

> 5% weight loss at 3 months with Orlistat predicted weight loss and improved cardiovascular risks at one year. > 2 to 4 kg weight loss with Sibutramine predicted 1 year weight loss:
> 2 kg in first month or > 4 kg at 3 months
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 27 Metab 2006;699-708
Weight Loss at One Year Based on Weight Loss at 3 Months

0
Mean % Weight Loss
< 4 kg
-5
-10
> 4 kg
-15 0 2 4 6 8 10 12
28
Months
Finer N, et al Diab Obes Metab 2006;8:206-213.
BUT All Drugs Have Adverse Events and Some Can Be Serious
29
Unintended Consequences of Drug Treatment for Obesity

Year Drug
1892 1932 1937 1968 1997 1998 2003 2007 2008 2010 Thyroid Dintrophenol Amphetamine Aminorex Phen/Fenfluramine Phenylpropanolamine Ma Huang (ephedra) Ecopipam (Dopamine) Rimonabant (CB-1) Sibutramine
Consequence
Hyperthyroidism Cataracts/Neuropathy Addiction Pulmonary Hypertension Valvulopathy Strokes Heart attacks/stroke Depression/Suicide Depression CVD Risk
30
Bray GA Battle of the Bulge, Dorrance Publishing 2007 p. 59
Would an Outcome Study Reduce these Adverse Events?

Adverse Event Idiopathic Primary Pulmonary Hypertension Pointes-de-Torsade Arrhythmia Valvular insufficiency Suicidality Stroke Cardiovascular disease Drugs Aminorex Fenfluramine Collagen-based low calorie diets Fenfluramine, dexfenfluramine Rimonabant Ecopipam Phenylpropanolamine Ephedra; sibutramine
31
Adverse Event Profile (Odds-Ratio)

Adverse Event ORL FLUOX BUPROP TOP Diarrhea/Constipation 54.8 1.85 1.37 1.08 Headache Nausea Fatigue Dry Mouth Nervous - CNS Depression Paresthesias Taste Change Upper Respiratory 1.18 0.95 ---0.33 ---1.35 3.27 2.83 -7.85 ----0.99 --3.26 0.98 ---1.22 --1.36 3.13 3.97 -20.2 11.1 1.76
32
Adapted from, Li , Z et al. Ann Int Med 2005;142:532-546
Outcomes Differ Between Drugs

Outcome - Change Waist Circumference Systolic BP Diastolic BP Heart Rate Total Cholesterol LDL-cholesterol HDL-cholesterol Triglycerides ORL -2.06* -1.52* -1.38* --0.32* -0.26* -0.03* -0.03 SIB -3.99* 1.69* 2.42* 4.53* --0.04* -0.18* RIM -3.89* -1.78* -1.23* --0.04 -0.05 0.10* -0.24*
33
Data are weighted mean differences; * = Confidence intervals do not cross 0

Adapted from Rucker D, et al BMJ 2007335:1194-1199
Sibutramine Reduces Weight, But Increases Blood Pressure: The Sibutramine Cardiovascular Outcome (SCOUT) Trial
34
Outline of SCOUT Trial

Randomized Phase
6-week Lead-in
Screening
Treatment Period Follow-up Period Up to 6 Years Contact with site Monthly visits for first 3 mos Every 3 months Followed by 3 monthly visits Beginning with Month 6 Sibutramine 10 mg or 15 mg Lifestyle and Placebo
Sibutramine 10 mg
Lead-in Randomization Period Baseline
Final Visit
35
James WP et al NEJM 2010363:9-5-91; Caterson I et al Obesity 2010;18:987-994
Weight Loss during the SCOUT Trial

100
Body Weight (kg)
Lifestyle
95
90 -4 0 4 8
Sibutramine
12 16 20 24
36
intervals of Treatment
James PT et al NEJM 2010; 363:9-5-917; FDA Briefing Document 15 Sept 2010
Primary Outcome Endpoint ITT Analysis 18

16 14 12 10 8 6 4 2 0 0 Incidence of Primary Outcome Events (%)
Primary Endpoint Nonfatal MI Nonfatal Stroke Resuscitation after cardiac arrest Cardiovascular death
11.4% Sibutramine 10.0% Placebo
18 24 36 48 Months Since Randomization
60
Kaplan-Meier Plot of Weight Loss by Response to Sibutramine

Incidence of Primary Outcome Event
14 12 10 8 6 4 2 0 0 20 40 60
14.0% Sibutramine < 5% Loss 9.5% Sibutramine > 5% Loss
Months Since Randomization
SCOUT Study comparing the 30% of patients randomized to sibutramine who lost >5% of their body weight against the 70% who lost < 5%
How Can We Mitigate the Risk 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 -1
Intermittent and Continuous Sibutramine

Placebo Interm ittent Continuous
Change in Body Weight (kg)
-2 -3 -4 -5 -6 -7 -8 -9 -10 0 4
12
18
24
30
36
42
48
Weeks
Run-In Randomized Treatment (N=1001)
40
Wirth & Krause JAMA 2001; JAMA 286(11): 1331-9.

41
Combination of Pramlintide and Phentermine on Body Weight

0
Weight Loss (kg)
Placebo Pramlintide
-5
-10
Pram + Phen
-15 0 10 20 30
Weeks of Treatment
Aronne L et al Obesity 2010;18:1739-1746
42

43
Fluoxetine Fails to Maintain Body Weight Loss

0
Weight Loss (kg)
Placebo -2
-4 Fluoxetine -6 0 10 20 30 40 50 60
44
Weeks
Goldstein et al IJO 1993;17:129-135

45
Metformin Treats Diabetes and Lowers Weight Over 10 Years

4
Weight Change (%)
2 0 -2 -4 -6 0
Placebo Never Adherent <50% Adherent >50% Adherent Highly Adherent
Placebo discontinued after an average of 3.2 years
10
46
Time since Randomization

DPPOS: Diabetes Care 2012:April with approval

47
Variability of Response to Therapy in Look AHEAD Study

0
Weight Loss (%)
-5 -10
10th % 25th % 50th % 75th %
-15
90th %
-20 0 2 4 6 8 10 12 14
Months of Treatment
Espeland ME et al Ann Epidemiol 2009;701-710
Conclusions
Excess weight, weight gain and central adiposity increase many health risks Weight loss improves the risk profile in almost all 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
But, ALL drugs have risks AND Not all patients respond equally to any given medication Most benefits from medication for obesity are achieved in 6 months Lifestyle-placebo effects vary between trials, weight loss from baseline might be a better criterion than weight loss below placebo to evaluate response.
50
Conclusions
Therefore: Physicians prescribing anti-obesity drugs should ascertain that patients are responding adequately, and if not modify treatment Several strategies can be used to mitigate potential risks, including intermittent treatment, combination therapy, selecting effective drugs and stopping treatment for unresponsive patients
51
brayga@pbrc.edu
52

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Pathophysiology of Obesity and CVD

CVD Mortality and Obesity:

Men (n=84,376) Women (n=217,857) Non-smokers Without known heart disease

28 30 22 25 Body Mass Index (BMI)

Calle EE et al. NEJM 341:1097,1999

Metabolic Pathophysiology of Obesity and CVD

The Role of Adipose Tissue and Adipose Tissue Distribution and

Visceral vs. Subcutaneous Adipose Tissue

Visceral vs. Subcutaneous

Visceral Adiposity: The Critical Adipose Depot

Subcutaneous Fat Abdominal Muscle Layer Intra-abdominal Fat

Waist Girth Tertiles (cm)

Body Mass Index Tertiles (kg/m2)

Relationship Between Visceral Adipose Tissue and Insulin Action

18 16 14 12 10 8 6 4 2 0 0 1,000 2,000 3,000 4,000 5,000 Women Men

Visceral adipose tissue volume per unit surface area (mL/m2)

Banerji et al. Am J Physiol 1997; 273: E425E432

Pathogenesis: -Cell Compensation and Decompensation and T2DM

Insulin Secretion (U/mL)

Normal Glucose Tolerance Impaired Glucose Tolerance Type 2 Diabetes

Insulin Action (mg/kg EMBS per minute)

Weyer C et al. J Clin Invest 104: 787, 1999

Hypertension Insulin Resistance Metabolism

HDL cholesterol small dense LDL

Glucose TNF- IL-6

Adiponectin Triglyceride (intramuscular droplet)

Eckel RH et al, Lancet 365:1415, 2005

The Link Between Insulin Resistance and Endothelial Dysfunction

IL-1, IL-6, TNF

Vasodilation Shear Stress Inflammation Atherosclerosis Thrombosis CRP PAI-1

Apo B:C-III:E-containing VLDL IDL (Sf 10-20) Remnants

removal of TG-rich lipoproteins

apo C-III VLD L

apo C-III TG Storage apo B-100 TG Synthesis SREBP-1c FFA

Pathogenesis of Decreased HDL Cholesterol in The Metabolic Syndrome

Inflammatory Markers and Insulin Resistance

Yudkin, JS et al, ATVB 19:976, 2001

Festa et al. Circulation 102:42-7, 2000

More Metabolic Syndrome

Cardiac Abnormalities in Obesity

adipositas cordis (cardiomyopathy of obesity)

Right ventricular hypertrophy

Arrhythmias, prolonged QTc, sudden death

Cardiovascular Adaptations in Obesity

Left ventricular end diastolic pressure Heart rate Cardiac output

Cardiac Abnormalities in Obesity

Tirosh A et al. NEJM 364:1315, 2011

Tirosh A et al. NEJM 364:1315, 2011

Cardiac Abnormalities in Obesity

adipositas cordis (cardiomyopathy of obesity)

Right ventricular hypertrophy

Myocardial Response to ObesIty and Insulin Resistance

Reduced cardiac function

Prolonged action potential Electrical remodeling

Hypertension and Obesity: NHANES III (1988-1994)

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

Mechanisms Relating Obesity to Hypertension

Narkiewicz K et al Obes Rev 7:155, 2006

Duration of Severe Obesity: Systolic Blood Pressure

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

Duration of Severe Obesity: LV End Diastolic Dimension

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

CVD Mortality, Hypertension in the Womens Health Initiative