Pharmacologic & Surgical Approaches

Nancy F. Krebs, MD, MS, FAAP

Pharmacologic Agents

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?

Use of Pharmacotherapy• Potential for significant adverse effects:

– Hypertension– Pulmonary hypertension– Psychological effects

• Currently available for pediatric use:– Sibutramine (Meridia)– Orlistat (Xenical)– (Metformin)

Anorectic Agents: Limit food intakeAnorectic 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

Sibutramine (Meridia)

Non-selective inhibitor of neuronal reuptake of serotonin and norepinephrine: appetite

suppressant

SibutramineSibutramine

• 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)

Sibutramine + Behavior TherapySibutramine + Behavior Therapy

Weight Changes Mean ± SD Range Wt (kg) -7.8 ± 6.3 -23.8 - +1.2 BMI (%) -8.5 ± 6.8 -24.4 - +1.1

Modest & variable improvement of lipid

and insulin parameters

Berkowitz et al, JAMA ‘03

(p=0.001)

Sibutramine -Side EffectsSibutramine -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**FDA Approved for patients over age 16

Orlistat (Xenical)

Pancreatic lipase inhibitor: fat malabsorption

OrlistatOrlistat• 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

-4

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0 3 6 9 12

WeekMcDuffie, 2002

Orlistat-Clinical TrialOrlistat-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

Chanoine, J.-P. et al. JAMA 2005;293:2873-2883.

Change in Weight

Chanoine et al, JAMA, 2005(p=0.001)

Placebo

Orlistat

Orlistat 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 lossChanoine et al, JAMA, 2005

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**FDA approved for children over age 12

Metformin

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

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

Metformin in Obese Adolescents

Effect of Metformin on Insulin in 0bese Adolescents

Freemark et al. Pediatrics, 2001

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

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

• 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 ChoicesSummary: Medication Choices

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?

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.”

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)

Bariatric Surgery

Rationale for Bariatric Surgery in Adolescents

• Persistence of pediatric obesity into adulthood – especially “extreme obesity” (BMI > 40, 200% IBW)

• Adolescents presenting with adult diseases, increased mortality

• Increases in obesity-related health care costs• Limited efficacy of behavioral (& pharmacologic)

approaches for the severely obese• Surgical weight loss ameliorates or resolves many

obesity related co-morbidities; durability of weight loss

RYGB: Roux en-Y gastric bypass

BPD: Biliopancreatic diversion

GP: GastroplastyDS: Duodenal

switch

Number of bariatric surgeries, USA

1996-2001

Livingston. Am J Surg 2004

Bariatric Surgery for Severely Overweight Adolescents:

Concerns and RecommendationsCriteria :

• 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

Inge, et al. Pediatrics 114:217, 2004

>30>30 >40>40 >50>50BMIBMI

YESYES

SeriousSeriousco-morbidity?co-morbidity?

NONO

Behavioral Behavioral ProgramProgram

““Consider”Consider”Bariatric SurgeryBariatric Surgery

Less SeriousLess Seriousco-morbidity?co-morbidity?

YESYES

NONO

Girls >13-14 Boys > 15-16

Bariatric Surgery for Severely Overweight Adolescents: Concerns and Recommendations

Inge, et al. Pediatrics 114:217, 2004

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

Inge, et al. Pediatrics 114:217, 2004

Timing of Surgical Treatment

• Sexual and skeletal maturation Sexual maturation- Tanner 3 or 4 Skeletal maturation –

age 13-14 y/o girls, 15-16 boys or have attained mid parental height

• Stage of cognitive development Acquired formal operations – thinking

about possibilities, consequences

Psychological Evaluation

• Structured interview w/ adolescent psychologist

• Age appropriate objective testing to assess Personality traits Cognitive maturity Depression Eating behaviors Weight related quality of life

Psychological Evaluation

• Contraindications substance abuse psychiatric disabilities including severe

eating disorders, mental impairment inability or unwillingness to follow

medical or nutritional recommendations or to maintain close long-term contact with health care providers

Roux-en-Y Gastric Bypass

Inge, et al. Pediatrics 114:217, 2004

•Create 15-30 ml gastric pouch

•Gastrojejunostomy impairs rapid gastric emptying

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)

Roux-en-Y Gastric Bypass

Bariatric Surgery: Experience Counts

1-19 cases; 6.2% mortality

20-85 cases; 0.73% mortality

86-220 cases; 0.37% mortality

•Surgeon experience and 30-day mortality for RYGP*

•Operative time, rates of leak & other complications after ~ 100 cases

*Flum, et al. J Amer Coll Surg, 2004

Inge et al. J Pediatr Surg, 2004

Weight Loss Following RYGB

N=10 N=2N= 4

BMI

Adults: 14 yr f/u

-36%*

Adoles: 14 yr f/u

- 27%**

* Pories, 1995

** Sugarman, 2003

Laparoscopic Adjustable Gastric BandLaparoscopic Adjustable Gastric Band

Adjustable Gastric Banding

Inge, et al. Pediatrics 114:217, 2004

Placed laparoscopically; adjustable and removable

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)

Adjustable Gastric Banding

Comparison of Procedures

Surgery Options ComparedSurgery Options Compared• RYGB

1-3 day LOS More extensive 1.5-3.5 hr operation Proven and favored

in U.S. Proven effective in

RCT 0.5% mortality* 17% morbidity*

• AGB 1 day LOS Less extensive 0.75-1.0 hr operation Favored worldwide;

new in the U.S Favorable results in

large case series 0.05% mortality* 7% morbidity*

* Comparisons from adults

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

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

Inge et al, J Peds, 2005

Acknowledgements

• Mel Heyman, MD, FAAP

• Thomas Inge, MD• Many, many

colleagues!

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”

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

GGActivity 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

GG: School Aged Child

Girls: 2 to 20 years

BMI BMI

BMI BMI

GG:Growth During

Infancy

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

Setting the Agenda: A Joint Proposition

↓GrazingEat at table

ContinueSports Family

Meals

↓Portions

? ?

Food Choices

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)

GG: School Aged Child

Girls: 2 to 20 years

BMI BMI

BMI BMI

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