Download Disclosures

The Role of Medications in the
Treatment of Pediatric Obesity
Considerations and Research
Aaron S. Kelly, Ph.D.
Department of Pediatrics
University of Minnesota Medical School
Disclosures
• I have received research funding support
from Amylin Pharmaceuticals (and Eli Lilly),
the manufacturer of exenatide, and have
served on a pediatric obesity advisory
committee for Novo Nordisk Pharmaceuticals,
the manufacturer of liraglutide
• I intend to discuss unapproved uses of
commercial products in my presentation
Overview
• Considerations regarding patient
selection for pharmacotherapy
• Severe obesity
• Medications evaluated for the treatment
of pediatric obesity
• Weight loss medication pipeline: brief
update on research and development
Patient Selection
• Considerations:
– Severity of obesity
– Risk factors/co-morbidities
– Family history (obesity, chronic disease)
– Pubertal development
– Age and executive function
Severe Pediatric Obesity
• Based upon age- and gender-specific
cutoffs
– <85th percentile = normal weight
– ≥85th<95th percentile = overweight
– ≥95th percentile = obese
– ≥1.2 times the 95th percentile or 35
kg/m2 = severe obesity
Severe Pediatric Obesity
• Fastest growing pediatric obesity
category
• Approximately 6% of US pediatric
population is severely obese – that’s an
average of 1 child in every U.S.
classroom!
Cardiovascular Risk Factors
Freedman, DS et al. J Pediatr 2007
Norris et al. Obesity 2011
Adiponectin
ANCOVA p<0.001
g/mL
20
15
10
NW
OW
OB
EO
140
120
100
ng/mL
25
Leptin
ANCOVA p<0.0001
80
60
40
5
20
0
0
BMI Groups
Kelly et al. Metab Syndr Relat Disord, In press
BMI Groups
NW
OW
OB
EO
Risk for Type 2 Diabetes
• Up to 25% of severely obese youth
seeking medical weight management
have impaired glucose tolerance
• Severe obesity is an independent
predictor of progression from IGT to
T2DM in adolescents
• The tempo of progression to T2DM may
be faster in adolescents than in adults
BMI Tracking to Adulthood
Freedman, DS et al. J Pediatr 2007
Treatment Approaches
• Earlier intervention generally leads to better
outcomes in obese youth
– Lifestyle modification
• Diet
• Physical activity
• Psychosocial support/management
– Medical management
•
•
•
•
(Sibutramine)
Orlistat
Metformin
GLP-1 receptor agonists
– Surgical management
• Roux en Y gastric bypass
• Laparoscopic gastric banding
Lifestyle Modification
Lifestyle Modification
• Few studies have focused on youth with
severe obesity
• Some studies suggest lifestyle
interventions are not as effective in
severely obese patients and durability of
effects are short-lived
Lifestyle Modification
• Results in intervention trials likely not
attainable in real-world clinical setting
• Many will not be willing or able to
implement necessary behavior
changes, especially over the long-term
• Even if “successful”, lifestyle
modification is not enough for most
• But, it should always be the
cornerstone of therapy
Pathophysiology of Obesity
Zanella et al. Arq Bras Endocrinol Metab 2009
Weight Loss Medications
• Unfortunate track-record
– Fenfluramine/Phentermine
– Rimonabant
– Sibutramine
• Result = stringent standards required by
FDA
Medications Evaluated in
Children/Adolescents
• Sibutramine
– Removed from market: CV concerns
• Orlistat
• Metformin
• Exenatide
Orlistat
• Trade name is Xenical (over-thecounter as Alli)
• Mechanism of action = lipase inhibition
• Approved by FDA for ages 12 and
above
• Administered orally TID with meals
Orlistat
• Approximately 5 studies to date in
children/adolescents
• Largest randomized, placebo-controlled
trial (N = 539) reported BMI reduction of
2.4% (mean baseline BMI was 36
kg/m2)
Orlistat
Chanoine et al. JAMA 2005
Orlistat
• CVD/metabolic risk factor improvement
– Small reduction in DBP
– No other risk factor improvement
• Side Effects
– Oily spotting
– Fecal urgency
– Abdominal pain
Metformin
• Trade names are Glucophage,
Fortamet, Glumetza
• Administered orally and available in
immediate- (BID) and extended-release
(QD) formulations
• Used for glycemic control in type 2
diabetes
• Weight-loss mechanism of action is
largely unknown
• Not approved by FDA for weight loss
Metformin
• A number of pediatric studies have
evaluated metformin as a weight loss
agent
• Only two randomized, placebocontrolled trials with BMI as prespecified endpoint
– Study in adolescents 13-18 years old reported 3% BMI
reduction
– Study in children ages 6-12 years old reported 3.2% BMI
reduction
Metformin
Wilson et al. Arch Pediatr Adolesc Med 2010
Metformin
Yanovski et al. Diabetes 2011
Metformin
• CVD/metabolic risk factor improvements
appear limited (some studies report
modest improvements in fasting insulin,
glucose, HOMA-IR)
• Delays onset of type 2 diabetes in
adults (DPP)
• Strong safety track-record but can
cause GI side effects (nausea, vomiting)
Exenatide
• Trade names are Byetta (BID) and
Bydureon (QW)
• Approved for use in adults with type 2
diabetes for glycemic control (not
approved for weight loss)
• Mode of administration: SC injection
• Probable weight-loss mechanisms
– Central effect on hypothalamus (appetite)
– Slowing of gastric motility (satiety)
Study Design
• Randomized, controlled (lifestyle modification),
crossover trial
• 12 children/adolescents (age 12.8 ± 2.0 yrs; 10 girls)
with severe obesity
• 3-months exenatide injection (5 mcg 1-mo; 10 mcg 2mo), 3-months control, randomized to order
• Outcome variables:
–
–
–
–
–
–
BMI, body weight, body fat (DXA)
Glucose tolerance (2-hr oral glucose tolerance test)
Lipids
Blood pressure
Adipokines
Endothelial function (EndoPAT)
Baseline Characteristics
Kelly et al. Obesity 2012
Treatment Effect by Group
Kelly et al. Obesity 2012
Kelly et al. Obesity 2012
Oral Glucose Tolerance
Kelly et al. Obesity 2012
Adverse Events
• Reported Adverse Events
– Nausea in 4/12
– Vomiting in 3/12
– Headache 3/12
– Injection site bruising 1/12
– No reports of hypoglycemia or pancreatitis
• Compliance was excellent (mean of all
completers = 98% of required doses)
Kelly et al. Obesity 2012
Ongoing Study
• Randomized, double-blind, placebo-controlled,
clinical trial (dual-center: U of M and Children’s
Hospitals and Clinics of MN)
• 26 adolescents (ages 12-19) with severe obesity
• 3-month RCT followed by 3-month open-label
extension
• Outcome variables:
–
–
–
–
BMI, body weight, body fat (DXA, at U of M only)
Lipids
BP
Fasting glucose/insulin, HbA1c
Use of Medications in the Clinic
• Ideally within the confines of weight
management specialty care
• Current options offer modest additional
efficacy beyond what can be achieved
with lifestyle modification alone
Use of Medications in the Clinic
• Orlistat considerations
– Minimal weight loss
– Often intolerable side effects
• Metformin considerations
– Minimal/modest weight loss
– Moderate GI side effects
– Potential role in patients with IR (hyperinsulinemia, IGT, AN)
• Exenatide (GLP-1 RA) considerations
– Preliminary evidence suggests minimal/modest weight loss
– Moderate GI side effects
– Potential role in patients with IGT
Drug Development for Obesity
•
•
•
•
Phentermine+Topiramate (Qnexa)
Lorcaserin (Lorqess)
Bupropion+Naltrexone (Contrave)
Many compounds in phase I-III trials
Drug Development for Obesity
• Combination approaches likely to be
most effective
• Medications would ideally have
beneficial effects beyond weight loss
Valentino et al. Clin Pharmacol Ther 2010
Minnesota Pediatric Obesity
Consortium
• Minnesota Pediatric Obesity Consortium (MNPOC):
–
–
–
–
University of Minnesota
Mayo Clinic
Children’s Hospitals and Clinics of Minnesota
International Diabetes Center at Park Nicollet
• Mission is to provide platform for conducting
high-quality clinical pediatric obesity studies
and education for MN providers who manage
obese youth