pharmacologic surgical approaches

1: Pharmacologic & Surgical Approaches Nancy F. Krebs, MD, MS, FAAP

3: Pharmaco-therapy For severely overweight children, the risk of complications is great Adjunctive therapy may be helpful in achieving weight loss & in treating co-morbidities Must be used in conjunction with behavioral, dietary, and activity approaches Cost effectiveness: coverage for drugs, not for conservative measures?

4: Use of Pharmacotherapy Potential for significant adverse effects: Hypertension Pulmonary hypertension Psychological effects Currently available for pediatric use: Sibutramine (Meridia) Orlistat (Xenical) (Metformin)

5: Anorectic Agents: Limit food intake Should complement diet/exercise program Modest effects on total weight loss Variable responses (may reflect heterogeneity in etiology) Most benefit achieved within first 4 mo Regain of weight the norm when drug therapy stopped

6: Sibutramine (Meridia) Non-selective inhibitor of neuronal reuptake of serotonin and norepinephrine: appetite suppressant

7: Sibutramine Berkowitz et al. JAMA 289:1805, 2003 82 obese adolescents (13-17 yr; BMI Z-score + 2.4) All received behavior (& diet) therapy Randomized to sibutramine vs. placebo 74 completed first 6 months, 62 completed 1 year) (after 6 mo, open label)

8: Sibutramine + Behavior Therapy

9: Sibutramine -Side Effects 19/43 with mild hypertension and tachycardia; 5 required discontinuation Other side effects Insomnia, anxiety, headache, depression, risk of serotonin syndrome in combination with other CNS drugs No data in absence of behavioral intervention **FDA Approved for patients over age 16

10: Orlistat (Xenical) Pancreatic lipase inhibitor: fat malabsorption

12: Orlistat Inhibits pancreatic lipase and increases fecal fat losses 20 adolescents, BMI 44.1 ± 12.6, with at least one comorbidity; behavioral therapy + orlistat in open-label fashion x 3 mo

13: Orlistat-Clinical Trial Inclusion criteria: Male or female 12–16 years BMI: minimum 28.5 – 32 (age dependent) Exclusion criteria: BMI ? 44 kg/m2 Body weight ? 130 kg or < 55 kg Diabetes mellitus 539 subjects studied • all received lifestyle intervention • randomized to orlistat vs. placebo x 1 year

14: Change in Weight

15: Orlistat Clinical Trial Modest responses (+ 0.53 kg vs +3.14 kg at 1 yr); slight ? BMI vs ? in placebo) Wt loss ? 5%: 26% vs 16% Wt loss ? 10%: 13% vs 4.5% Dropout rates ~ 1/3 both groups No significant differences in lipid profiles or glucose tolerance/insulin Weight loss associated w/ greater fat loss

16: Orlistat Clinical Trial No apparent differences in response by sex or ethnic/racial group Side effects: no micronutrient (f.s. vit) deficiencies GI Symptoms: 50% w/ fatty stools 29% w/ oily spotting ? ? to 8.5% 8.8% w/ fecal incontinence ? ? to 2.0% Requires education of patients **FDA approved for children over age 12

17: Metformin

18: Metformin ? hepatic gluconeogenesis and glucose production; ? hepatic insulin sensitivity Attenuates lipogenic state of hyperinsulinism (obesity ? ? insulin resistance/hyperinsulinism) ? food intake ? fat stores (SQ > visceral?), improves lipid profiles 25 % reduction in cumulative 3 yr incidence of T2DM in adults; ? CV morbidity & mortality in adults w/ T2DM

19: Metformin in Obese Adolescents Freemark et al. Pediatrics 107:e55, 2001 32 obese adolescents with insulin resistance and positive family history of T2DM (29 completed) Double-blind, randomized to metformin vs. placebo x 6 months No dietary restriction

20: Metformin in Obese Adolescents

22: Metformin in Obese Adolescents Side effects: Transient abdominal discomfort or diarrhea (< 1 mo) (Lactic acidosis (rare) in adults with chronic cardiac, hepatic, renal or GI disease) Urinary losses of B vitamins: use daily MVI in all metformin patients **Approved for Type 2 diabetes mellitus; not yet approved for obesity

23: Metformin in Obese Adolescents Remaining questions: Effects on weight (fat mass) loss w/ medication +/- lifestyle changes Effects on hyper/dys-lipidemia unclear Longer-term studies w/ larger “n” underway – safety & efficacy

24: Sibutramine: beware CV effects; acts on CNS Orlistat: highly motivated, h/o significant fat intake; GI effects may be limiting fx Metformin: obese adolescent with insulin resistance obesity due to psychotropic drugs ? Summary: Medication Choices

25: Summary - Medications Additional (to behavioral + lifestyle Rx) positive effect of medication is modest on average, substantial for some Reimbursement? Lifestyle: often “no” Medications: more likely? Access: medications vs (+/-) lifestyle Duration of treatment? Compliance? Predictors of optimal choice?

26: Summary – MedicationsPediatric Nutrition Handbook (5th Ed): “Drug therapy in children is not recommended…currently no Food and Drug Administration (FDA)-approved medications for use in children < 16 years of age. “However, in some extremely obese adolescent patients with life-threatening morbidities, this approach may be necessary with the warning that…studies of the effectiveness of these drugs in children have not yet been reported.”

27: Medication Quandry: Is the glass ½ full or ½ empty? Reserve meds for the “extreme” situation &/or use only as “experimental”? or View as part of the armamentarium, knowing effect will be greater for some than others? (e.g. –24% vs +1% ? BMI)

28: Bariatric Surgery

31: Bariatric Surgery for Severely Overweight Adolescents: Concerns and Recommendations Criteria : Failed at least 6 months of organized weight management (as per PCP) Attained (or nearly) physiologic maturity BMI >40 with serious obesity-related comorbidity or BMI >50 with less severe comorbidities

33: Bariatric Surgery for Severely Overweight Adolescents: Concerns and Recommendations Criteria (cont): Commitment to comprehensive medical and psychologic evaluations before and after surgery Avoid pregnancy at least one year after surgery Be capable and willing to adhere to nutritional guidelines postoperatively Provide informed assent to surgical treatment Demonstrate decisional capacity Have supportive family environment

38: Advantages: Significant weight loss or lower BMI (~33%) one year post-op; generally sustainable (14 year f/u) Deterrence to carbohydrate ingestion Enhanced satiety Risks: Perioperative death (0.5%) (vs ABG: [.05%]) (adults) Other: intestinal leakage, thromboembolic disease, SBO, incisional hernia, cholelithiasis, PCM Micronutrient deficiencies: Fe, Ca, B1, B12, folate Late deaths also reported (up to 6 years post-op) Late weight regain? (up to 15% of pts)

39: Bariatric Surgery: Experience Counts

43: Advantages: Minimally invasive placement (laparoscopic) Less nutrient effect compared with RNYGB Adjustable (by MD – encourages f/u) Removable Disadvantages: ? Slower weight loss (max at 2-3 yr p-op) Finite lifetime (needs to be replaced) Long term results are unknown (only available for <10 years) Not yet approved by FDA for <18 y/o (not covered by insurance)

46: Surgical Outcomes (primarily based on adult data) ? mortality: Morbidly obese diabetic adults – 9 yr obs: 28% vs 9% w/o vs w/ bariatric surgery Improvement in dyslipidemia: 80% pts Hypertension: resolves 65%, improves 80% (may not be longstanding) T2DM: 75% pts remission; 85% pts ? disease burden ? Obstructive sleep apnea Psychological: ? depression, ? self concept/QOL

47: Research Considerations & Future Directions Long-term outcomes of bariatric surgery in adolescents remain to be defined Risk/benefit & timing of intervention: earlier “correction” of metabolic derangements (how early is too early?) Future efforts directed at determination of physiologic mechanisms alteration in appetite feeding behavior energy balance

48: Acknowledgements Mel Heyman, MD, FAAP Thomas Inge, MD Many, many colleagues!

49: GG 9-1/2 yr old girl, healthy Cc: Parents: concern about ?’g wt & effects on health Want pt to become more committed to health What is the problem? “She loves food; watches food network on cable, cookbooks, etc” Pt: eating makes her “feel better”

50: 9 yr old GG Diet hx: Brk: 2 sl pizza + ice cream (2 scoops) Lunch: double cheeseburger & fries Dinner: hamburger, bun, 2 scoops of ice cream Few limits; “doesn’t know when to stop eating” Often skips lunch, eats through evening

51: GG Activity history: Competitive jump roping, soccer – 2-4x/wk < 2 hr TV/d; computer < 1x/wk PMHX: benign; h/o hyperlipidemia FHx: BMI: Dad 26; Mom 22; + hx T2DM, obesity, hypertension, g.b. disease SHx: dad in health care admin; mom home full time ROS: mild joint c/o; o/w negative

52: GG: School Aged Child

54: GG Wt: 72 kg, Ht 146 Exam: positive acanthosis nigricans, o/w unremarkable except for overweight status Assessment: BMI = 33.7 (190% of ideal, c/w severe o.w.) At risk for insulin resistance, hyperlipidemia Multiple dietary problems Excessive portion sizes Lack of structure/limits on eating High risk foods in household

55: Setting the Agenda: A Joint Proposition

56: GG: Recommendations Diet & Eating ? portions/size of breakfast (max 2-3 pancakes or 1 piece french toast; Eat only in the kitchen, w/ adult present “Close the kitchen” between meals/snacks Keep ice cream out of house Activity – continue soccer & jump rope Behavior Kept “health calendar” Weigh self q 2 wk (set a start date)

57: GG: School Aged Child

58: Diet Control Stop all sugar beverages (soda AND juice) Drink water and low fat milk Healthy snack = protein + fruit/veg (e.g. peanut butter and banana) Wait 20 min for second helpings Reduce TV time