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

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5

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15

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25NWOWOBEO

ANCOVA p<0.001

BMI Groups

g/m

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Leptin

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20

40

60

80

100

120

140NWOWOBEO

ANCOVA p<0.0001

BMI Groups

ng

/mL

Kelly et al. Metab Syndr Relat Disord, In press

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-the-counter 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, placebo-controlled trials with BMI as pre-specified 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 2-

mo), 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 (MN-POC):– 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