Pediatric obesity Can medications help? Dr mahtab ordooei

Dramatic rise of pediatric obesity

Early recognition and treatment of pediatric obesity reduce a lifetime of morbidity and mortality

What can we do? At EVERY visit for EVERY patient, record a BMI : get a table or BMI calculator Properly label the problem : Underweight < 18.5 Normal weight 18.5 - 25 Overweight >25 to < 30 Obese 30 to < 40 Morbidly Obese 40 or more

BMI in Kids BMI //apps.nccd.cdc.gov/dnpabmi/calculator.aspx Labels are based on BMI percentiles, not weight %-iles : BMI //apps.nccd.cdc.gov/dnpabmi/calculator.aspx > 75th to 84th Caution and close observe 85th to 94th Overweight 95th & more Obese

Plotted BMI-for-Age Age= 4 y, 4 wks Height=106.4 cm (41.9 in) Measurements: BMI BMI Girls: 2 to 20 years Age= 4 y, 4 wks Height=106.4 cm (41.9 in) Weight=15.7 kg (34.5 lb) BMI=13.9 BMI-for-age= 10th percentile Normal BMI BMI

Sinha et al NEJM 2003

Obesity comorbidities Cardiovascular: hypertension, coronary artery disease, angina pectoris, congestive heart failure Cerebrovascular: stroke Hyperlipidemia Metabolic syndrome/type 2 DM Cholelithiasis Gout, uric acid nephrolithiasis Osteoarthritis Obstructive sleep apnea, hypoventilation Hyperandrogenism, hirsutism, irregular menses, complications of pregnancy, stress incontinence Malignancies: breast, endometrium, colon, prostate Increased surgical risk Psychological disorders

Pediatric weight management A challenge for patients, their families, physicians Family-based lifestyle intervention is the core treatment modality

Obesity Treatment Pyramid Diet Physical Activity Lifestyle Modification Pharmacotherapy Surgery Obesity treatment pyramid The clinical approach to obesity can be viewed as a pyramid consisting of several levels of therapeutic options. All patients should be involved in an effort to change their lifestyle behaviors to decrease energy intake and increase physical activity. Lifestyle modification also should be a component of all other levels of therapy. Pharmacotherapy can be a useful adjunctive measure for properly selected patients. Bariatric surgery is an option for patients with severe obesity, who have not responded to less-intensive interventions. The number of obese patients who require a specific level of treatment decreases as one moves up the pyramid.

Body weight reductions of more than5% require Numerous clinical visits Access to health-promoting food Physical activity environments Motivation

Pharmacotherapy May be considered in obese children if a formal program of intensive lifestyle modification has failed to limit weight gain

Anti Obesity Drugs The decision to initiate drug therapy should be made only after a careful evaluation of risks and benefits

Anti Obesity Drugs May be a helpful But along with Diet Exercise Behavior modification. Most patients regain their weight when their weight-loss drugs are stopped.

When to start treatment? BMI greater than 30 kg/m2 BMI ≥95th percentile for age and sex in children BMI between the 85th and 95th with significant and severe co morbidities BMI ≥99th percentile for age and sex pediatrics 2007 Rev Endocr Metab Disord 2009

When the treatment is successful? Success measured by Degree of weight loss Improvement in associated risk factors.

When the treatment is successful? Weight loss should exceed 2 kg during the first month of drug therapy Fall more than 5 percent below baseline by three to six months Weight remain at this level to be considered effective

What happens after weight loss ? A weight loss of 5 to 10 percent reduce the risk for diabetes  and CVD in high risk patients weight loss of 10 to 15 percent is considered a very good response weight loss exceeding 15 percent is considered an excellent response.

Can they cure obesity? Drug therapy does not cure obesity. Obese subjects given drugs should be advised that when the maximal therapeutic effect is achieved, weight loss ceases. When drug therapy is discontinued, weight is regained.

Classification of anti obesity drug Current anti obesity drug can be classified into three categories Agents that suppress appetite peripherally acting agents that impair absorption Agents that affect energy expenditure

Sympathomimetic Drugs Sibutramine Block Reuptake norepinephrine ,serotonin, dopamine increased risk of heart attack and stroke, MI was removed from 2010

Sympathomimetic Drugs Bupropion Norepinephrine and dopamine reuptake inhibitor that is used as an atypical antidepressant Several adult trials have documented weight loss

Antidepressants Fluoxetine and sertraline Serotonin reuptake inhibitors May facilitate weight loss in the short run.

FDA non approved drugs Fenfluramine Because of associated cardiac valve &pulmonary hypertension Raising concerns about the long-term use of other serotoninergic preparations (eg, fluoxetine) in children Removal of ephedra and phenylpropanolamine because of cardiovascular concerns Pediatric 2007

Sympathomimetic Drugs Tolerance is achieved within 2 weeks. Contraindications Angina Atherosclerotic disease, Cardiac arrhythmia Hyperthyroidism Concomitant use of MAOI

.

Drugs That Alter Fat Digestion Orlistat (Xenical ,venustat) FDA approved Orlistat in obese adolescents Aged 12 to 16 years use in significant obesity comorbidities

Orlistat Recommended dose 60- 120 mg three times daily Vitamin A 5000 IU Vitamin D 400IU Vitamin E 300 IU Vitamin K 25mg food intake >2 h apart from orlistat

Mode of action inhibit a gastric and pancreatic lipases Hydrolyze dietary fat to free fatty acids and glycerol Systemic absorption is minimal Fecal fat excretion is increased. Curr Opin Endocrinol Diabetes Obes 2015

Orlistat Reduces fatty acid absorption by ∼30% (16 g/day) in persons consuming a 30% fat diet It has a modest effects on triglycerides and HDL-cholesterol

Orlistat 2–3 kg/m2 loss in BMI 0.5 to 4 kg/m2 Curr Opin Endocrinol Diabetes Obes 2015 Ann Pharmacother 2015

Orlistat Current effect of orlistat along with behaviour therapy may not be more effective than behaviour therapy alone >12 years Curr Opin Endocrinol Diabetes Obes 2015

Side Effects Of Orlistat Fecal incontinence, oily spotting, and flatus with discharge, steatorrhea, Gallstones,, nausea, bloating, liquid stools, fecal urgency and abdominal cramping

Contraindication of Orlistat Malabsorption syndrome Cholestasis Advanced liver disease Failure to decrease dietary fat Frequent meals at restaurant

Future anti-obesity drugs Exenatide is GLP-1 receptor agonist Recommended for adults with T2DM increases insulin secretion while decreasing glucagon secretion. increasing satiety and decreasing appetite. Reduced BMI by 1.1 to 1.7 kg/m2 Ann Pharmacother 2015

Case study 11 children aged 8–19 years. 5ug twice a day given SC 3-month, open-labelled study BMI> 95th 11 children aged 8–19 years. 5ug twice a day given SC BMI reduction of 1.7 kg/m2 Improvements in insulin and glucose markers Curr Opin Endocrinol Diabetes Obes 2015

a randomized, double blind, case–control study with lifestyle changes The effect of glucagon-like peptide-1 receptor agonist therapy on body mass index in adolescents with severe obesity a randomized, double blind, case–control study with lifestyle changes children aged 12–19 years 10ug twice a day The most common adverse events Nausea, vomiting, diarrhea, headaches.

Glucagon-like peptide-1 receptor  Exenatide elicited a greater reduction in percent change in BMI compared with placebo JAMA Pediatr 2013

Diabetic Drugs Metformin Stimulation of glucose uptake by the muscle Activate of AMP-activated protein kinase which results in Stimulation of glucose uptake by the muscle Inhibits hepatic gluconeogenesis Diminishes insulin resistance and hyperinsulinemia, Decrease lipogenesis in adipose tissues. Small reduction in total cholesterol level (∼0.26 SD). Ann Pharmacother 2015

Metformin& weight loss BMI reductions of 0.17 to 1.8 kg/m2 Ann Pharmacother 2015

Metformin Recommended for those aged 10 years and older who have T2DM is not FDA approved for the obese children It is useful for insulin resistance, or PCOS Doses :500mg-2500mg PO twice a day .

Metformin Effective in children aged 6–12 years with insulin resistance A supplement of vitamin and calcium is recommended to improve B12 absorption during metformin treatment

Metformin Side effects Abdominal discomfort, which improves when the medication is taken with food. flatulence, bloating,nausea ,diarrhea ,Lactic acidosis Vitamin B12 deficiency; therefore, a multivitamin is recommended. lactic acidosis, which has been observed in adults but not seen in pediatric patients.

Metformin Contraindication Heart, kidney, and liver disease, Severe illness Decreased perfusion Stop for surgical and radiological procedure Patients with liver function tests less than three times the upper limit of normal are considered appropriate to take the medication.

Leptin Leptin gene defect Is a cause of severe early-onset obesity. Children have severe hyperphagia and obesity Daily subcutaneous injections effects on fat mass, hyperinsulinemia ,hyperlipidemia is not approved by FDA

At low physiological doses Starting at 0.02-0.04 ug/kg/day Effects of Recombinant Leptin Therapy in a Child with Congenital Leptin Deficiency At low physiological doses Starting at 0.02-0.04 ug/kg/day Given subcutaneously at 6 pm. Might benefit from leptin therapy. Arq Bras Endocrinol Metab. 2010

Growth hormone is FDA-approved in Prader-Willi syndrome only for the increasing height velocity is not FDA approved for the treatment of obesity.

Conclusion If patients do not lose at least 5% of their weight loss medications demonstrate only modest efficacy %3–9 within the first 6 months Concerns of weight rebound with the discontinuation If patients do not lose at least 5% of their baseline weight within 3 months unlikely to benefit from that treatment

THANK YOU FOR YOUR ATTENTION