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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
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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
-Cell Failure
400
300
200
100
Insulin Resistance
10
TG
and
VLDL
FFA
Insulin
IL-6
SNS
{
CRP
FFA
Fibrinogen
PAI-1
Prothrombotic State
11
{
-
Insulin Glycogen
FFA
CO2
Vascular Endothelium
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)
VLDL
TG
LPL
Hypertriglyceridemia
Obesity
Insulin Resistance FFA
Eckel RH, ATVB, 31:1946, 2011
Fat
Mass
LPL
production of HDL2
HDL3 clearance
15
15
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
uric acid and gout Cognitive dysfunction Polycystic ovarian syndrome Non-alcoholic fatty liver disease Obstructive sleep apnea
17
19
Autonomic dysfunction
20
21 20
Poirier P and Eckel RH: The Heart and Obesity, Chpt 83, 2000, In: Hurst's The Heart
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
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
26
Myocardial ischemia
Microangiopathy Endothelial dysfunction
Parasympathetic Sympathetic
Metabolic factors
Dysglycemia Intracellular triglyceride accumulation
Myocardial inflammation
Oxidative stress AGEs Mitochondrial dysfunction Apoptosis
Cardiac arrhythmias
27
5 10 15 20 25 30
years
30
5 10 15 20 25 30
years
31
32
33
Autonomic dysfunction
34
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
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
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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
37
Changes in Cardiac Geometry and Function Two Years after Bariatric Surgery
38
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
0.12
BMI
(kg/m2)
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.
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Thank You!
80 C a s e s /1 0 0 0 p e rs o n -y r 60 40 20 0
<20
Knowler: Am J Epidem, 1981
-25
-30
-35
-40
40
2
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
Placebo n = 1082
Metformin n = 1073
Total n = 3,234
participants
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
10
0 0 1 2 3 4
31%
58%
11.0
0
PLAC
7.8
MET
4.8
ILS
8
Metformin
Placebo
0 White (n=1768) African American (n=645) Hispanic (n=508) American Indian (n=171) Asian (n=142)
9
10
DPP: Hazard Rate for Developing Diabetes As A Function of Weight Change From Baseline
20
10
15
Average Risk
0
-15
-10
-5
+5
16
placebo
11
metformin
6
-10 -8 -6 -4 -2 0 2 4 Change from baseline weight (kg) 6
12
CC
49%
CT
41%
TT
9%
Metformin
Lifestyle
13
16
17
Metformin
C. Age Group 25 - 44 y
Lifestyle
Placebo Metformin Lifestyle
Placebo
2
Metformin
Lifestyle
2
All ages
Age 25-44
-6
-8
10
-8 0
-6
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
19
20
21
22
23
24
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
27
28
5-9
10-14
15-19
29
Age (years)
20-24
25-29
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
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
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
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
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
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
Composite #2
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
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
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
20
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
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%)
0 -1 -2 -3 -4 -5 -6 -7 -8 -9 0 1 2
Year
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%
26
NS
28
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
Year
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%
6 8 10 12 14 16 18
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
p < .02
p < .05
2500 2000
Meal Replacements
Kcal/wk of Activity
100 80 60 40 20 0
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
35
Baseline weight, gender, age, ethnicity, insulin Treatment attendance Dietary intake or physical activity Year 1 weight loss
36
37
Look AHEAD Research Group. Arch Int Med 2010;170:1566-75
38
DSE Baseline Y1 BL Y2 BL Y3 BL
DSE ILI 3 4
Y4 BL
40
Look AHEAD Research Group. Arch Int Med 2010;170:1566-75
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
0 -1 -2 -3 -4 -5 -6 -7 -8 -9 0 1 2
Year
Y3 BL Y4 BL
43
0 DSE -1 ILI
-2
-3
-4 0 1 2 Year 3 4
Baseline Use
DSE N=1872 95% 96% 95% 95% ILI N=1895 94% 94% 94% 94%
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
5 4 3 2 1 0 0 1 2 Year 3 4
Y3 BL Y4 BL
47
-20
Y2 BL Y3 BL
-30 0 1 2 Year 3 4
Y4 BL
48
49
LDL Cholesterol (mg/dl) Change from Baseline Repeated Measures Adjusting for Clinic, Baseline Level, and Medication Use
Average
DSE ILI
50
51
Weight Loss of 5 10 % produces significant improvements in CVD risk factors at year 1 (except LDL-C)
52
53
54
55
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
55% 45% 46% 35% 26% 18% 8% 25% 18% 23% 10% 9% 4%
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
32
Male
16
Female
8 15 20 25 30 35 40
5
45
Mass Index
Idiopathic intracranial hypertension Stroke Cataracts Coronary heart disease Diabetes Dyslipidemia Hypertension Severe pancreatitis Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate
Diabetes
NAFLD
CVD
Osteoarthritis
GB Disease
Cancer
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
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
0.015
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
12
50
25
HDL CHOL
-40 -80
TG Insulin 0 5 40
40
15 0 -15
No. of subjects
89 .
82 133 71
66
67 127 121 86
-5
-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)
14
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
Mobility Score
Time
Time
Rejeski J et al NEJM 2012;March 29; with approval; on-line after 5 PM March 28 NEJM.org
30.5% Moderate
Foster et al. Diabetes Care. 2009 Jun;32(6):1017-9.
33.5 % Mild
17
Change in AHI
8 DSE 4
DSE
0 -4 ILI
ILI
-8 -12 0 1 2 Year 4
19
10
20
30
DB
40
50
60
70
80
DB
90 100 110
Week
Preferred
Adequate
15
10
-10
-5
0 0
+5
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
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
50 0 0 3 6
Gastric Bypass
12
Months
Months
Change in BMI
40
M ed Therapy
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
26
< 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
Consequence
Hyperthyroidism Cataracts/Neuropathy Addiction Pulmonary Hypertension Valvulopathy Strokes Heart attacks/stroke Depression/Suicide Depression CVD Risk
30
Sibutramine Reduces Weight, But Increases Blood Pressure: The Sibutramine Cardiovascular Outcome (SCOUT) Trial
34
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
Final Visit
35
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
60
SCOUT Study comparing the 30% of patients randomized to sibutramine who lost >5% of their body weight against the 70% who lost < 5%
0 -1
-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
Placebo Pramlintide
-5
-10
Pram + Phen
-15 0 10 20 30
Weeks of Treatment
Aronne L et al Obesity 2010;18:1739-1746
42
Placebo -2
-4 Fluoxetine -6 0 10 20 30 40 50 60
44
Weeks
Goldstein et al IJO 1993;17:129-135
2 0 -2 -4 -6 0
10
46
-5 -10
-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