Pharmacotherapy and Surgery Treatment for the Severely Obese Adolescent

Sibutramine 

Originally studied as an antidepressant, sibutramine is a serotonin and norepinephrine re-uptake inhibitor, with metabolites (M1 and M2) that weakly inhibit dopamine, causing satiety when taken at therapeutic doses. Multiple trials in adults have demonstrated that the appetite suppressant effects of sibutramine lead to weight loss, including the Sibutramine Trial of Obesity Reduction and Maintenance (STORM) trial, a long-term trial demonstrating a sustained weight loss while taking sibutramine for up to 2 years (Hansen et al., 2001, James et al., 2000, Rucker et al., 2007, Wirth and Kraus, 2001). Sibutramine also has been effective in a randomized controlled trial (RCT) study in the treatment of binge eating disorder (Wilfley et al., 2008). Sibutramine is a schedule IV–controlled medication that is approved by the FDA for use in children aged 16 years and older.

Sibutramine in combination with behavior therapy has been demonstrated in randomized, double-blind, placebo-controlled trials to induce significantly more weight loss than placebo combined with behavior therapy (BT) in adolescents (Berkowitz et al., 2003, Berkowitz et al., 2006). Berkowitz et al. (2003) measured the effectiveness of sibutramine and BT in adolescents aged 13 to 17 years (n = 82) with a mean weight loss of 7.8 kg (P = .001) in the study group, compared with 3.2 kg in the placebo group. The sibutramine treatment group reported significant reduction in hunger (P = .002) over the placebo group (Berkowitz et al., 2003). A large (n = 498), multi-center (33 sites), 12-month RCT studied behavior therapy plus 10 mg of sibutramine or placebo in adolescents aged 12 to 16 years (Berkowitz et al., 2006). In this study the sibutramine dose was increased to 15 mg at month 6 if initial BMI was not reduced by 10% (Berkowitz et al., 2006). BMI change for the sibutramine plus behavior therapy was -3.1 kg/m2 versus -0.3 kg/m2 for placebo plus BT (difference, -2.9 kg/m2 [95% CI, -3.5 to -2.2 kg/m2]; P < 0.001) (Berkowitz et al., 2006). Additionally, improvements in triglyceride levels, high-density lipoprotein cholesterol levels, insulin levels, and insulin sensitivity (P < 0.001 for all) were seen in the study subjects (Berkowitz et al., 2006). Treatment with sibutramine combined with BT (diet, exercise, and group therapy) is warranted in adolescents aged 16 years or older who fail to achieve results with a formal intensive lifestyle modification program (August et al., 2008). Dosing of sibutramine and monitoring parameters during therapy is found in Table 2.

Table 2. Dosing of medications approved to treat adolescent obesity

	Generic name	Trade name	Recommended dose	Adverse effects	Monitoring
	Orlistat	Xenical, Alli	120 mg PO TID with meals∗ (OTC dose 60 mg TID)	Flatulence, oily anal discharge, fecal incontinence, vitamin malabsorption	Vitamin D levels; patient should take a multivitamin
	Sibutramine	Meridia	5 to 15 mg PO daily	Tachycardia, hypertension, insomnia, palpitations, anxiety, nervousness, depression	Monitor HR, BP, drug interactions with other serotonergic agents

BP, Blood pressure; HR, heart rate; OTC, over the counter; PO, by mouth; TID, three times a day.

∗ Dose can be skipped if meal does not contain fat.

The most common adverse effects of sibutramine in both adolescents and adults are headache (30.3%), dry mouth (17.1%), constipation (11.5%), and insomnia (10.7%). There is a dose-related increase in heart rate and blood pressure, with a dose of 10 to 15 mg/day causing an average increase in systolic and diastolic blood pressure of 1.0 to 1.7 mm Hg and an average increase in heart rate of 3.7 beats/minute (Berkowitz et al., 2006). Blood pressure should be taken at baseline and at regular intervals throughout therapy.

Sibutramine's action inhibiting serotonin and norepinephrine re-uptake is similar to that of some antidepressants, and adolescents should be monitored for suicide ideation. Drug interactions are possible with any other medication causing tachycardia or hypertension, including cold medications such as pseudoephedrine or phenylephrine. Serotonin syndrome may occur with monoamine oxidase inhibitors or other serotonergic drugs, including selective serotonin reuptake inhibitors and triptan migraine medications (sumatriptan [Imitrex]); thus, simultaneous use of sibutramine and other serotonergic agents is not recommended. Patients need to be educated regarding drug interactions prior to beginning therapy and throughout therapy.

Orlistat 

Orlistat is a reversible inhibitor of pancreatic and gastric lipases, the enzymes required for fat absorption. A dose of 120 mg three times a day with meals inhibits fat absorption approximately 30%. Orlistat is minimally absorbed and is eliminated in the feces. Administration of orlistat to adults (n = 892) combined with a dietary intervention (calorie controlled, 30% from fat) leads to a significantly greater weight loss over 12 months compared with placebo and dietary intervention (8.6 kg versus 5.81 kg, P < .001) (Davidson et al., 1999). The use of orlistat in adolescents demonstrated similar results in an RCT over 54 weeks where the study group had significantly decreased BMI, waist circumference, and body fat compared with placebo (Chanoine, Hampl, Jensen, Boldrin, & Hauptman, 2005). In a meta-analysis of three orlistat studies in adolescents, McGovern et al. (2008) determined a small to moderate effect on obesity outcomes (-0.29; CI = - 0.46 to -0.12; I2 -0%); this effect is consistent with a loss in BMI of 0.7 kg/m2 (CI = 0.3-1.2 kg/m2).

Orlistat is approved by the FDA for use in children as young as 12 years of age and is available as an over-the-counter medication called Alli (60-mg capsule), as well as the prescription form Xenical (120-mg capsule). The main adverse effects of orlistat are related to its effect on fat absorption, causing abdominal discomfort and flatus. The most upsetting adverse effect in patients is oily stools and oily fecal discharge due to unabsorbed fats being eliminated in the stool. Up to 26% of patients experience oily fecal discharge, although the incidence of this effect may improve with continued use (Roche Pharmaceuticals, 2008). The flatus and oily discharge leading to staining of underwear is a common reason for discontinuance of the medication.

Orlistat is taken three times a day with meals containing fat. The medication may be taken up to 1 hour after the meal. Patients should be on a diet restricting fats to no more than 30% of total intake. If the meal does not contain fat, the orlistat dose may be skipped. Orlistat may reduce the absorption of some fat-soluble vitamins; therefore, the manufacturer recommends that users take a multivitamin daily, administered at least 2 hours before or after the orlistat dose (Roche Pharmaceuticals, 2008). A concern for adolescents taking orlistat is the need to take it with all meals, requiring taking the medication while at school. Dosing and monitoring of orlistat therapy is found in Table 2.

Medications Not Approved By the FDA for Treatment of Obesity in Adolescents 

Metformin. The biguanide anti-diabetic drug metformin suppresses hepatic glucose production and decreases insulin resistance and may cause weight loss, particularly loss of abdominal fat in patients with insulin resistance or polycystic ovarian syndrome contributing to their obesity. In a meta-analysis of three studies of metformin use for weight loss in adolescents, the analysis did not demonstrate statistical significance, although that may be due to differences in study design between the studies (August et al., 2008, McGovern et al., 2008). Metformin also may counter weight gain in adolescents who gain weight while taking atypical antipsychotic agents (August et al., 2008). Consultation with a pediatric endocrinologist is warranted if one is considering the use of metformin in obese adolescents.

Topiramate. The anti-seizure medication topiramate (Topamax) has a well-documented adverse effect of weight loss in both adults and children. The Endocrine Society guidelines clearly state that topiramate should not be used as a weight loss medication because of its effects on the central nervous system, causing drowsiness and impaired cognition (August et al., 2008).

Rimonabant. The endocannabinoidis system acts to modulate energy balance regulation and adipocyte secretion. There are two cannabinoid receptors, CB1 and CB2, with CB1 located in the brain, adipose tissue, and throughout the body. When the CB1 receptor is stimulated, such as when cannabis is used, the person experiences hunger. Rimonabant is a CB1 receptor blocker, working centrally and peripherally to reduce hunger, food intake, and adipocyte secretion. The end result is weight loss. Rimonabant was approved for use outside the United States and initially received a favorable review from the FDA in 2006, but because of concerns regarding severe depression-related adverse events, the FDA did not license it for use in the United States. In October 2008, the European Medicines Agency recommended that doctors not prescribe rimonabant because of the risk of serious psychiatric effects, including risk of suicide (Drugdevelopment-technology.com, 2009).

Bariatric Surgery 

Bariatric surgery is one of the fastest growing surgical procedures in the United States, growing by 400% from 1998 to 2002 (Encinosa, Bernard, Steiner, & Chen, 2005). Bariatric surgery has two main components—restriction of the size of the stomach and bypassing part of the intestines to reduce absorption of nutrients—or a combination of the two. Bariatric surgery represents a long-term solution to obesity, with a demonstrated decrease in adult rates of type II diabetes, including complete remission in 73% of study subjects of their type II diabetes in a group monitored for 2 years after adjustable gastric band surgery (Dixon et al., 2008). An overall decrease in mortality for all reasons was seen in 40% of adult patients undergoing bariatric surgery compared with control subjects in a systematic review conducted by Ferchak and Meneghini (2004).

The two procedures most commonly used in adolescents are laparoscopic adjustable gastric banding and gastric bypass surgery. Standards of care set for adolescent bariatric surgery have been developed by the International Pediatric Endosurgery Group (IPEG), including patient selection criteria, preoperative care and postoperative care guidelines (IPEG Standards and Safety Committee, 2008). The pediatric nurse practitioner (PNP) or clinician may consider referral for bariatric surgery in any patient with a BMI over 50 or a BMI over 40 with comorbidities, including type II diabetes (see Table 1). Regardless of the procedure, the adolescent should be managed by a multidisciplinary team including surgeons skilled in adolescent bariatric surgery, nutritionists, and mental health specialists. Pediatric nurses and PNPs often are an integral part of the team. Primary care of adolescent bariatric surgery patients will be discussed later in this article.

Laparoscopic Adjustable Gastric Banding 

The laparoscopic adjustable band (LAP-BAND, Realize) is a silicone band that is placed via laparoscopic surgery around the upper portion of the stomach, resulting in a very small pouch available for food. The band's diameter is adjustable, allowing controlled weight loss or “loosening” of the band for times of increased nutritional need such as pregnancy. The laparoscopic adjustable band is a restrictive procedure that does not affect food absorption. The patient needs to make multiple visits to the surgical team to have the volume of the band adjusted throughout the weight loss period and periodically afterward. In a review and meta-analysis of six laparoscopic adjustable band studies by Treadwell, Sun, and Scholles (2008), the random effects analysis of adolescent weight loss was 10.6 to 13.7 BMI units (95% CI) in patients monitored for 1 to 3 years.

Laparoscopic adjustable banding is a fairly safe procedure, with no in-hospital or postoperative deaths reported in a meta analysis of 352 operations conducted by Treadwell, Sun, and Scholles (2008). Band slippage requiring surgical correction is the most common postoperative complication, with slippage rates varying from center to center and ranging from 7% to 15% in adult patients (Ferchak & Meneghini, 2004). Band slippage requiring surgical correction was reported in 3% of adolescents in a meta analysis of adolescent studies (Treadwell et al.). Hiatal hernia, cholecystitis, and physical intolerance of the band also have been reported. While the laparoscopic adjustable band is intended for long-term treatment, the band may be removed and the stomach is returned to its normal anatomical state and function. It must be noted that adjustable gastric banding has not been approved by the FDA for use in adolescents and is considered investigational at this time.

Gastric Bypass Surgery 

Gastric bypass surgery is a procedure that is both restrictive and affects absorption of nutrients. The most common procedure is the Roux-en-Y procedure gastric bypass (RYGB), where a small stomach pouch is fashioned and a bypass of the small intestine is created to decrease absorption leading to rapid weight loss. Patients have substantial and sustained loss of excess body weight, with excess body weight defined as the difference between preoperative BMI and a healthy BMI of 25 to 30 (Levitsky, Misra, Boepple & Hoppin, 2009). In a meta-analysis of four studies of RYGB surgery outcomes in adolescents, the random-effects summary statistic ranged from 17.8 to 22.3 BMI units (95% CI) lost postoperatively (Treadwell et al., 2008). The RYGB procedure leads to greater excess weight loss than does the gastric band, but it also has a higher surgical complication rate (Levitsky et al.).

Complications from gastric bypass surgery are both from the surgery itself and because of the changes in absorption of micronutrients caused by the bypass itself. Early postoperative complications include pulmonary embolism, wound infection, and anastomotic leak (Treadwell et al., 2008, Levitsky et al., 2009). There have been no reported in-hospital deaths in adolescents who underwent gastric bypass surgery (Treadwell et al.). Long-term complications include nutritional deficits because of decreased absorption of micronutrients including iron, calcium, vitamin B12, and thiamine (Levitsky et al.). Iron deficiency anemia and mild beriberi have been reported in adolescents after gastric bypass surgery (Treadwell et al.). These nutritional deficits can be anticipated and treated with a multivitamin containing iron. An understanding of normal adolescent development is key in preventing nutritional deficits, with Haynes et al. (2008) recommending that the PNP or nurse member of the bariatric team assume adolescents have problems remembering to take their multivitamin and help them develop a plan for compliance.