Transcript Adolescent-Obesity - Rex Moulton

Adolescent Obesity
Objectives
• Definition of overweight in youth
• Prevalence and trends
• Health implications
• Behavioral and pharmacological treatment
What Is BMI?
• Body mass index (BMI) = weight (kg)/height (m2)
• Or: BMI = [weight (pounds) X 703]/height (in2)
• BMI is an effective screening tool; it is not a
diagnostic tool
• For children, BMI is age and gender specific, so
BMI-for-age is the measure used for youth
BMI-for-Age Cutoffs
for Children and Adolescents
≥ 95th percentile
Overweight
85th to < 95th percentile
Risk of overweight
< 5th percentile
Underweight
For Children, BMI Changes with Age
Boys: 2 to 20 years
BMI
BMI
BMI
BMI
Example:
95th Percentile
Tracking
Age
BMI
2 yrs
4 yrs
9 yrs
13 yrs
19.3
17.8
21.0
25.1
Tracking BMI-for-Age from Birth to
18 Years with Percent of Overweight
Children Who Are Obese at Age 25
100
BMI ≥ 85th
BMI < 85th
BMI ≥ 95th
83
% obese as adults
77
75
80
69
60
67
55
52
36
40
26
20
16 17
15
19
12
11
10
9
10 to 15
15 to 18
0
Birth
1 to 3
3 to 6
6 to 10
Age of child (years)
Whitaker et al. NEJM. 1997;337:869-873.
Childhood Obesity:
Risk for Disease
• Cardiovascular disease
• Gallbladder disease
• Lipid disorders
• Obstructive sleep apnea
• Hypertension
• Orthopedic problems
• Diabetes Mellitus type 2
• Metabolic syndrome
• Cancer (breast, uterine, prostate, and colon)
• Sudden death
• Psychosocial distress/body image disparagement
Example: Adults overweight as teens had an increased
relative risk of all-cause morbidity and of coronary heart
disease
Must A, et al. NEJM 1992;327:1350-1355.
Metabolic Syndrome in Childhood
• 439 obese children versus 51 overweight or non-obese
(aged around 11-12 years)
• 3 of following
− BMI > 97th
− Triglyceride > 95th
• Systolic BP > 95th
• HDL < 5th
− Impaired glucose tolerance
• Prevalence
− 38.7% of moderately obese BMI SDS > +2 < +2.5
− 49.7% of severely obese BMI > +2.5
• Prevalence increases directly with degree of obesity
Weiss R et al. NEJM:2004;350,23.
Metabolic Syndrome
Associated with Insulin Resistance
Weiss et al 2004.
BMI Is Associated with Metabolic
Syndrome Risk Factors in Children
and Adolescents
Pearson Correlation Coefficients of Variables in the Analysis
Variable
BMI z score
Correlation coefficient
P value
LogLogTransformed
BMI Transformed
HDL
Insulin
z score Triglycerides Cholesterol Resistance
1.0
Weiss et al. JAMA. 2004
0.04
0.33
- 0.14
0.001
0.31
< 0.001
Weiss R et al. NEJM 2004
Glucose
Blood Pressure
Baseline At 2 Hr Systolic Diastolic
0.08
0.08
0.12
0.007
0.13
0.003
- 0.01
0.82
Increasing Prevalence of Pediatric
Type 2 Diabetes Mellitus in the US
• 15 years ago Type 2 diabetes mellitus
accounted for less than 3% of all new cases of
diabetes in children and adolescents in the USA
• The figure now stands at 45%
• Estimated that Type 2 diabetes will exceed Type
1 in childhood within 10 years*
* Report of American Academy of Pediatrics. 2003.112.
Etiology of Obesity
• Increased caloric consumption
• Sedentary lifestyle
• Genetic predisposition
• Medications: psychotropics, steroids
Long-Term Effects of Treating
the Parent + Child (8 – 11 y/o)
25
Parent plus child
Child alone
Non-specific control
Change in %age overweight
20
15
10
5
0
-5
-10
-15
-20
-25
-12
0
12
24
36
48
60
72
84
96
Months
Epstein, Valoski, Wing & McCurley. Health Psychology. 1994;13:373-383.
108
120
132
Previous Behavioral/Diet/Exercise Approaches
to Weight Management in Adolescents
• Few controlled studies on the treatment of adolescent obesity
• Comprehensive family-based behavioral programs are the
most studied interventions
• Behavior therapy: self-monitoring, goal setting, positive
reinforcement, stimulus control, contingency management
focused upon changing eating and physical activity habits
• The inclusion of parents in treatment is less clear than for the
treatment of children; parents are usually included.
• Most studies report weight losses of only 1 to 4 kg
• Participants typically remain obese at the end of studies
• New approaches are needed
Berkowitz et al. JAMA 2003; 289: 1805-1812.
0
Weight Loss (kg)
-1
Child Alone
-2
Mother-Child Alone
-3
Mother-Child Together
-4
-5
0
1
2
3
4
Months
Wadden TA, Stunkard AJ, Rich L, Rubin CJ, Sweidel G, McKinney S. Pediatrics. 1990; 85(3):345-52.
Obesity Pharmacotherapy:
NHLBI Adult Recommendations
• “Appropriate weight-loss drugs can augment
diet, physical activity, and behavior therapy in
weight loss”
• BMI  30 or  27 with co-morbidities
• Pharmacotherapy should only be given in
conjunction with lifestyle modification
National Institutes of Health. Obes Res. 1998;6(suppl 2):51S–209S.
Behavioral and Pharmacological
Treatment Combined
• Behavioral treatment helps the overweight person
to develop skills to cope with an environment
which promotes overeating and inactivity
• Pharmacological treatment may minimize the
effects of biological factors relating to weight gain
• Behavioral and pharmacological treatments
appear to be additive in adult studies
Wadden TA. Berkowitz RI, Sarwer DB, Prus-Wisniewski R, Steinberg C. Arch Gen Internal Med
2001;161:218-227.
Obesity Pharmacotherapy
Systemically Acting
System
Mechanism
Examples
CNS
Noradrenergic
Stimulates norepinephrine and
dopamine release
Phentermine
CNS
Noradrenergic & serotonergic
Blocks norepinephrine, serotonin and
dopamine reuptake
Sibutramine
Nonsystemically Acting
System
Mechanism
Examples
Digestive
Inhibition of lipase
Orlistat
There have been no comparative safety and efficacy trials between orlistat and
sibutramine or phentermine.
Refer to Physicians’ Desk Reference for other products.
Mechanisms of Action
Sibutramine’s Active Metabolites Block
Serotonin and Norepinephrine Reuptake
S
S
Reuptake
S
Serotonin
S = sibutramine
 = norepinephrine
 = serotonin
S
S
Reuptake
Norepinephrine
S
Ryan DH et al. Obes Res. 1995;3(suppl 4):553S.
Behavior Therapy and Sibutramine for
the Treatment of Adolescent Obesity:
A Randomized Controlled Trial
Robert I Berkowitz, MD, Thomas A Wadden, PhD,
M Tershakovec, MD, Joanna L Cronquist, BA
JAMA 2003; 289:1805-1812
Support: NIH, Abbott Laboratories
Andrew
Behavior Therapy and Sibutramine for
the Treatment of Adolescent Obesity:
A Randomized Controlled Trial
• 6 month randomized, double-blind, placebo-controlled
evaluation of efficacy and safety of sibutramine (final
dose 15 mg) when added to a comprehensive familybased behavioral program
• Open label sibutramine months 7 – 12
• Objectives: Percent change in BMI, hunger and
disinhibition of eating (Stunkard Messick Eating
Inventory), adherence to self-monitoring, lipids, insulin,
HOMA, BP, pulse, adverse events
Berkowitz et al, JAMA 2003; 289: 1805-1812.
Sibutramine Dosage Titration
• Week 1: placebo
• Week 2: sibutramine 5 mg or placebo
• Week 3: sibutramine 10 mg or placebo
• Week 7: sibutramine 15 mg or placebo
• If systolic or diastolic BP increased from
baseline by ≥ 10 mm Hg or pulse increased by
15%, dose decreased by 5 mg decrements
Berkowitz et al, JAMA 2003; 289: 1805-1812.
Family-Based
Bbehavioral Therapy Program
• Phase 1
− 13 weekly group sessions followed by
− 6 biweekly group sessions
• Phase 2
− Biweekly group sessions months 7 – 9
− Monthly group sessions months 10 – 12
• Behavior therapy: self-monitoring, goal setting, positive
reinforcement, stimulus control, slowing eating rate, parents
involved
• Dietary recommendation: 1200 – 1500 kcal/day, 30% fat,
15% protein
• Physical activity target of 120 minutes per week (e.g. walking)
Berkowitz et al, JAMA 2003; 289: 1805-1812.
Characteristics of Aadolescents
at Baseline
Placebo + BT
(n = 39)
Sibutramine + BT
(n = 43)
Female
24 (61.5)
31 (72.1)
Male
15 (38.5)
12 (27.9)
White
24 (61.5)
21 (48.8)
Black
13 (33.3)
21 (48.8)
Other
2 (5.2)
1 (2.3)
14.1 (1.2)
14.1 (1.3)
Weight, mean (SD), kg
105.3 (16.2)
102.0 (14.7)
Height, mean (SD), cm
166.2 (8.4)
164.6 (7.7)
BMI, mean (SD)
38.0 (3.6)
37.5 (4.0)
Sex, No. (%)
Race, No. (%)
Age, mean (SD), yrs
Berkowitz et al, JAMA 2003; 289: 1805-1812.
Mean Percentage Change in Initial BMI
(Intention-to-Treat Analysis)
0
Placebo + BT
(n = 39)
-1
% change in BMI
-2
-3
-4
-5
***
-6
*** P = 0 .001
-7
Sibutramine + BT
(n = 43)
-8
-9
-10
0
3
Month of Treatment
Berkowitz et al, JAMA 2003; 289: 1805-1812.
***
6
Percentage of Adolescents Achieving
5%, 10%, and 15% Rreductions in BMI
at Mmonth 6
% change in BMI
Placebo + BT, months 1-6
Sibutramine + BT, months 1-6
70
60
50
40
30
20
10
0
63*
* P = 0.02
40*
36
19*
15
3
> 5%
Berkowitz et al, JAMA 2003; 289: 1805-1812.
> 10%
> 15%
Self-Monitoring and Percentage
Change in BMI at Month 6
High self-monitoring
Low self-monitoring
0
% change in BMI
-2
(n = 16)
-4
-6
-8
-10
(n = 23)
(n = 25)
-12
-14
(n = 18)
-16
Placebo + BT
Berkowitz et al, JAMA 2003; 289: 1805-1812.
Sibutramine + BT
Mean Percentage Change in Initial BMI
(Intention-to-Treat Analysis)
% change in BMI
0
Placebo + BT
(n = 39)
-1
-2
-3
-4
-5
***
-6
-7
-8
-9
-10
Placebo + BT group received
sibutramine during months 7 – 12
*** P = 0 .001
Sibutramine + BT
(n = 43)
0
3
***
6
Placebo controlled
9
All subjects received sibutramine
Month of Treatment
Berkowitz et al, JAMA 2003; 289: 1805-1812.
12
Change (%) in Lipids at
Month 6 (n = 74) and Month 12 (n = 62)†
% change
10
8
6
4
2
Triglyceride
-10
-12
HDL
cholesterol
LDL
cholesterol
7.6
****
Baseline
values
(mg/dL)
2.3
(101.7)
0
-2
-4
-6
-8
Total
cholesterol
(165.5)
(99.8)
(45.4)
***
-3.2
* **
-9.3 -9.0
12 months
-2.5
-2.3
†
Berkowitz et al, JAMA 2003; 289: 1805-1812.
6 months
**
-4.6
* P = 0.02
**P = 0.05
***P = 0.01
****P = 0.001
Pooled data (no significant difference between
placebo + BT and sibutramine + BT groups)
Change (%) in Insulin, Glucose and HOMA
at Months 6 (n = 74) & 12 (n = 62)†
Insulin
(27 U/mL)
Serum glucose
(90.3 mg/dL)
HOMA
(6.1)
(Baseline values)
0
-1.9 -2.6
% change
-5
-10
6 months
*
-12.8
**
-15
-14.8
***
-20.2
-20
†
-25
12 months
Pooled data (no significant difference between
placebo + BT and sibutramine + BT groups)
Berkowitz et al, JAMA 2003; 289: 1805-1812.
* P = 0.02
** P = 0.01
***P < 0.001
***
-22.8
Blood Pressure (Mean mm Hg)
140
Mean BP (mmHg)
P = 0.02
120
100
P = 0.06
Systolic
80
60
Diastolic
40
20
BT + placebo
BT + sibutramine
Sibutramine added to
placebo group
0
Baseline
Month 3
Berkowitz et al, JAMA 2003; 289: 1805-1812.
Month 6
Month 12
Pulse Rate (mean beats/min)
Pulse rate (beats/min)
90
85
80
P < 0.001
P = 0.007
P < 0.001
75
70
65
60
55
BT + placebo
BT + sibutramine
Sibutramine added to
placebo group
50
Baseline
Month 3
Berkowitz et al, JAMA 2003; 289: 1805-1812.
Month 6
Month 12
Reasons for Discontinuation
(Entire Study)
Reason
Increases in blood pressure and/or pulse
( BP alone = 1; BP & pulse = 4; Pulse alone = 1)
#
6
Ecchymoses
2
Ventricular premature beats
1
Rash of unclear etiology
1
Total number of subjects
10
Berkowitz et al, JAMA 2003; 289: 1805-1812.
Mechanism of Action: Orlistat1,2
• Inhibition of lipases by
orlistat blocks
systemic
absorption of dietary
fat2
• Unabsorbed fat is
excreted into feces
(up to one-third of
ingested fat)2
1. Zhi et al. J Clin Pharmacol. 1995;35:1103-1108.
2. Zhi et al. Clin Pharmacol Ther. 1994;56:82-85.
Three-Month Tolerability of Orlistat in
Adolescents with Obesity-Related
Comorbid Conditions
McDuffie JR, Calis KA, Uwaifo GI, Sebring NG,
Fallon EM, Hubbard, Yanovski JA.
Obesity Research. 2002;10:642-650
Objective
• Study safety, tolerability, and potential efficacy of
orlistat in adolescents with obesity and its
comorbid conditions
Mc Duffie JR, et al. Obesity Research. 2002;10:642-650.
Research Methods and Procedures
• 20 adolescents
– Age: 14.6 ± 2.0 yrs
– BMI: 44.1 ± 12.6 kg/m2
• Subjects took orlistat (120 mg 3 times daily) and a
multivitamin for 3 months
• Subjects were simultaneously enrolled in a 12-week
lifestyle modification program, with emphasis on:
– Diet
– Exercise
– Behavior modification
Mc Duffie JR, et al. Obesity Research. 2002;10:642-650.
Results
• 85% completed treatment
– Took 80% of prescribed medication
• Adverse effects generally mild
– Limited to GI effects observed in adults
Mc Duffie JR, et al. Obesity Research. 2002;10:642-650.
Results (cont.)
Variable
Weight
Baseline
3 months
123.4 ± 43.0 119.0 ± 43.1
Body Mass Index
44.1 ± 12.4
(BMI) kg/m2
42.2 ± 13.0
Net change
Significance
-4.4 ± 4.6 kg
p < 0.001
-1.9 ± 2.5 kg/m2
p < 0.0002
Total Cholesterol
177.8 ± 41.2 156.6 ± 34.2 -21.3 ± 24.7 mg/dL
(mg/dL)
p < 0.001
LDL cholesterol
(mg/dL)
p < 0.0001
120.2 ± 30.1 102.9 ± 29.5 -17.3 ± 15.8 mg/dL
Mc Duffie JR, et al. Obesity Research. 2002;10:642-650.
Results (cont.)
Variable
Baseline
Fasting
2 hours
3 months
Fasting
2 hours
Net Change Significance
Glucose
(mg/dL)
101.7±38.3 123.1±64.2
86.3±6.4
106.4±21.5
-15.4±7.4
p < 0.003
Insulin
(µU/ml)
34.0±16.3
20.3±10.6
94.3±85.4
13.7±19.0
p < 0.02
117.0±71.7
Mc Duffie JR, et al. Obesity Research. 2002;10:642-650.
Summary
• Comorbid conditions associated with obesity in this patient sample
included:
– Hyperinsulinemia: 100%
– Hyperlipidemia: 20%
– Hypertension: 10%
– Type 2 diabetes: 5%
– Impaired glucose tolerance: 5%
• In adolescents, short-term treatment with orlistat in the context of a
behavioral program is well-tolerated and has a side effect profile
similar to that observed in adults
• True benefit versus conventional therapy remains to be determined
in placebo-controlled trials
Mc Duffie JR, et al. Obesity Research. 2002;10:642-650.
Conclusions
• Overweight is defined by BMI ≥ 95th percentile
for age and gender
• Increased co-morbidities, including metabolic
syndrome and type 2 diabetes mellitus with
increasing BMI
• Increasing prevalence of overweight among
youth
• Overweight tracks from childhood to adulthood
Conclusions
• Additive effects of behavior + sibutramine in adolescents
for weight loss by month 6 in teens
• Continuation of sibutramine resulted in maintenance of
weight loss by month 12
• Blood pressure and pulse effects (n = 19), similar to
those in adults, resolved through dose reduction (n =
15) in BT + sibutramine group
• Significant improvements in lipids, insulin and HOMA
• Orlistat: Promising initial uncontrolled study of weight
loss with orlistat
• Orlistat: improvements in lipids, insulin