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The Role of Medications in the Treatment of Pediatric Obesity Considerations and Research The Role of Medications in the Treatment of Pediatric Obesity.

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Presentation on theme: "The Role of Medications in the Treatment of Pediatric Obesity Considerations and Research The Role of Medications in the Treatment of Pediatric Obesity."— Presentation transcript:

1 The Role of Medications in the Treatment of Pediatric Obesity Considerations and Research 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

2 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

3 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

4 Patient Selection Considerations: –Severity of obesity –Risk factors/co-morbidities –Family history (obesity, chronic disease) –Pubertal development –Age and executive function

5 Severe Pediatric Obesity Based upon age- and gender-specific cutoffs –<85 th percentile = normal weight –≥85 th <95 th percentile = overweight –≥95 th percentile = obese –≥1.2 times the 95 th percentile or 35 kg/m 2 = severe obesity

6 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!

7 Cardiovascular Risk Factors Freedman, DS et al. J Pediatr 2007

8 Norris et al. Obesity 2011

9 Kelly et al. Metab Syndr Relat Disord, In press

10 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

11 BMI Tracking to Adulthood Freedman, DS et al. J Pediatr 2007

12 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

13 Lifestyle Modification

14 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

15 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

16 Pathophysiology of Obesity Zanella et al. Arq Bras Endocrinol Metab 2009

17 Weight Loss Medications Unfortunate track-record –Fenfluramine/Phentermine –Rimonabant –Sibutramine Result = stringent standards required by FDA

18 Medications Evaluated in Children/Adolescents Sibutramine –Removed from market: CV concerns Orlistat Metformin Exenatide

19 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

20 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/m 2 )

21 Orlistat Chanoine et al. JAMA 2005

22 Orlistat CVD/metabolic risk factor improvement –Small reduction in DBP –No other risk factor improvement Side Effects –Oily spotting –Fecal urgency –Abdominal pain

23 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

24 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 years old reported 3% BMI reduction –Study in children ages 6-12 years old reported 3.2% BMI reduction

25 Metformin Wilson et al. Arch Pediatr Adolesc Med 2010

26 Metformin Yanovski et al. Diabetes 2011

27 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)

28 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)

29 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)

30 Baseline Characteristics Kelly et al. Obesity 2012

31 Treatment Effect by Group Kelly et al. Obesity 2012

32

33 Oral Glucose Tolerance Kelly et al. Obesity 2012

34 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

35 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

36 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

37 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

38 Drug Development for Obesity Phentermine+Topiramate (Qnexa) Lorcaserin (Lorqess) Bupropion+Naltrexone (Contrave) Many compounds in phase I-III trials

39 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

40 Minnesota Pediatric Obesity Consortium Minnesota Pediatric Obesity Consortium (MN- POC)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


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