TREATMENT Obesity THE GOAL OF THERAPY
The primary goals of treatment are to improve obesity-related comorbid conditions and to reduce the risk of developing future comorbidities. Information obtained from the history, physical examination, and diagnostic tests is used to determine risk and develop a treatment plan (Fig. 21-1). The decision of how aggressively to treat the patient and which modalities to use is determined by the patient’s risk status, expectations, and available resources. Not all patients who are deemed obese by BMI alone need to be treated, as exemplified by the concepts of obesity paradox or the metabolically healthy obese. However, patients who present with obesity-related comorbidities and who would benefit from weight loss intervention should be managed proactively. Therapy for obesity always begins with lifestyle management and may include pharmacotherapy or surgery, depending on BMI risk category (Table 21-5). Setting an initial weight-loss goal of 8–10% over 6 months is a realistic target. LIFESTYLE MANAGEMENT
Obesity care involves attention to three essential elements of lifestyle: dietary habits, physical activity, and behavior modification. Because obesity is fundamentally a disease of energy imbalance, all patients must learn how and when energy is consumed (diet), how and when energy is expended (physical activity), and how to incorporate this information into their daily lives (behavioral therapy). Lifestyle management has been shown to result in a modest (typically 3–5 kg) weight loss when compared with no treatment or usual care. Diet Therapy
The primary focus of diet therapy is to reduce overall calorie consumption. Guidelines from the National Heart, Lung, and Blood Institute recommend initiating treatment with a calorie deficit of 500–1000 kcal/d compared with the patient’s habitual diet. This reduction is consistent with a goal of losing ~1–2 lbs per week. The calorie deficit can be instituted through dietary substitutions or alternatives. Examples include choosing smaller portion sizes, eating more fruits and vegetables, consuming more whole-grain cereals, selecting leaner cuts of meat and skimmed dairy products, reducing consumption of fried foods and other foods with added fats and oils, and drinking water instead of sugar-sweetened beverages. It is important that dietary counseling remain patient centered and that the goals set be practical, realistic, and achievable.
The macronutrient composition of the diet will vary with the patient’s preference and medical condition. The 2010 U.S. Department of Agriculture Dietary Guidelines for Americans, which focus on health promotion and risk reduction, can be applied to treatment of overweight or obese patients. The recommendations include maintaining a diet rich in whole grains, fruits, vegetables, and dietary fiber; consuming two servings (8 oz) of fish high in omega 3 fatty acids per week; decreasing sodium intake to <2300 mg/d; consuming 3 cups of milk (or equivalent low-fat or fat-free dairy products) per day; limiting cholesterol intake to <300 mg/d; and keeping total fat intake at 20–35% of daily calories and saturated fat intake at <10% of daily calories. Application of these guidelines to specific calorie goals can be found on the website www.choosemyplate.gov. The revised Dietary Reference Intakes for Macronutrients released by the Institute of Medicine recommends that 45–65% of calories come from carbohydrates, 20–35% from fat, and 10–35% from protein. The guidelines also recommend daily fiber intake of 38 g (men) and 25 g (women) for persons over 50 years of age and 30 g (men) and 21 g (women) for those under age 50.
Since portion control is one of the most difficult strategies for patients to manage, the use of pre-prepared products such as meal replacements is a simple and convenient suggestion. Examples include frozen entrees, canned beverages, and bars. Use of meal replacements in the diet has been shown to result in a 7–8% weight loss.
Numerous randomized trials comparing diets of different macronutrient composition (e.g., low-carbohydrate, low-fat, Mediterranean) have shown that weight loss depends primarily on reduction of total caloric intake and adherence to the prescribed diet, not the specific proportions of carbohydrate, fat, and protein in the diet. The macronutrient composition will ultimately be determined by the patient’s taste preferences, cooking style, and culture. However, the patient’s underlying medical problems are also important in guiding the recommended dietary composition. The dietary prescription will vary according to the patient’s metabolic profile and risk factors. A consultation with a registered dietitian for medical nutrition therapy is particularly useful in considering patient preference and treatment of comorbid diseases.
Another dietary approach to consider is based on the concept of energy density, which refers to the number of calories (i.e., amount of energy) a food contains per unit of weight. People tend to ingest a constant volume of food regardless of caloric or macronutrient content. Adding water or fiber to a food decreases its energy density by increasing weight without affecting caloric content. Examples of foods with low-energy density include soups, fruits, vegetables, oatmeal, and lean meats. Dry foods and high-fat foods such as pretzels, cheese, egg yolks, potato chips, and red meat have a high-energy density. Diets containing low-energy-dense foods have been shown to control hunger and thus to result in decreased caloric intake and weight loss.
Occasionally, very low-calorie diets (VLCDs) are prescribed as a form of aggressive dietary therapy. The primary purpose of a VLCD is to promote a rapid and significant (13- to 23-kg) short-term weight loss over a 3- to 6-month period. The proprietary formulas designed for this purpose typically supply ≤800 kcal, 50–80 g of protein, and 100% of the recommended daily intake for vitamins and minerals. According to a review by the National Task Force on the Prevention and Treatment of Obesity, indications for initiating a VLCD include the involvement of well-motivated individuals who are moderately to severely obese (BMI, >30 kg/m2), have failed at more conservative approaches to weight loss, and have a medical condition that would be immediately improved with rapid weight loss. These conditions include poorly controlled type 2 diabetes, hypertriglyceridemia, obstructive sleep apnea, and symptomatic peripheral edema. The risk for gallstone formation increases exponentially at rates of weight loss >1.5 kg/week (3.3 lb/week). Prophylaxis against gallstone formation with ursodeoxycholic acid (600 mg/d) is effective in reducing this risk. Because of the need for close metabolic monitoring, VLCDs usually are prescribed by physicians specializing in obesity care. Physical Activity Therapy
Although exercise alone is only moderately effective for weight loss, the combination of dietary modification and exercise is the most effective behavioral approach for the treatment of obesity. The most important role of exercise appears to be in the maintenance of the weight loss. The 2008 Physical Activity Guidelines for Americans (www.health.gov/paguidelines) recommend that adults should engage in 150 min of moderate-intensity or 75 min a week of vigorous-intensity aerobic physical activity per week, performed in episodes of at least 10 min and preferably spread throughout the week. Focusing on simple ways to add physical activity into the normal daily routine through leisure activities, travel, and domestic work should be suggested. Examples include walking, using the stairs, doing housework and yard work, and engaging in sports. Asking the patient to wear a pedometer or accelerometer to monitor total accumulation of steps or kcal expended as part of the activities of daily living is a useful strategy. Step counts are highly correlated with activity level. Studies have demonstrated that lifestyle activities are as effective as structured exercise programs for improving cardiorespiratory fitness and weight loss. A high level of physical activity (>300 min of moderate-intensity activity per week) is often needed to lose weight and sustain weight loss. These exercise recommendations are daunting to most patients and need to be implemented gradually. Consultation with an exercise physiologist or personal trainer may be helpful. Behavioral Therapy
Cognitive behavioral therapy is used to help change and reinforce new dietary and physical activity behaviors. Strategies include self-monitoring techniques (e.g., journaling, weighing, and measuring food and activity); stress management; stimulus control (e.g., using smaller plates, not eating in front of the television or in the car); social support; problem solving; and cognitive restructuring to help patients develop more positive and realistic thoughts about themselves. When recommending any behavioral lifestyle change, the patient should be asked to identify what, when, where, and how the behavioral change will be performed. The patient should keep a record of the anticipated behavioral change so that progress can be reviewed at the next office visit. Because these techniques are time-consuming to implement, their supervision is often undertaken by ancillary office staff, such as a nurse-clinician or registered dietitian. PHARMACOTHERAPY
Adjuvant pharmacologic treatments should be considered for patients with a BMI ≥30 kg/m2 or—for patients who have concomitant obesity-related diseases and for whom dietary and physical activity therapy has not been successful—a BMI ≥27 kg/m2. When an antiobesity medication is prescribed, patients should be actively engaged in a lifestyle program that provides the strategies and skills needed to use the drug effectively, since such support increases total weight loss.
Medications for obesity have traditionally fallen into two major categories: appetite suppressants (anorexiants) and gastrointestinal fat blockers. Appetite-suppressing medications have primarily targeted three monoamine receptor systems in the hypothalamus: noradrenergic, dopaminergic, and serotonergic receptors. Two new appetite suppressants were approved by the U.S. Food and Drug Administration (FDA) in 2012: lorcaserin and phentermine/topiramate (PHEN/TPM) extended release. Gastrointestinal fat blockers reduce the absorption of selective macronutrients, such as fat, from the gastrointestinal tract. Centrally Acting Anorexiant Medications
Anorexiants affect satiety (the absence of hunger after eating) and hunger (the biologic sensation that prompts eating). By increasing satiety and decreasing hunger, these agents help patients reduce caloric intake without a sense of deprivation. The target site for the actions of anorexiants is the ventromedial and lateral hypothalamic regions in the central nervous system (Chap. 20). The biologic effect of these agents on appetite regulation is produced by augmentation of the neurotransmission of three monoamines: norepinephrine; serotonin (5-hydroxytryptamine, or 5-HT); and, to a lesser degree, dopamine. The classic sympathomimetic adrenergic agents (benzphetamine, phendimetrazine, diethylpropion, mazindol, and phentermine) function by stimulating norepinephrine release or by blocking its reuptake. Among the anorexiants, phentermine has been the most commonly prescribed; there is limited long-term data on its effectiveness. A 2002 review of six randomized, placebo-controlled trials of phentermine for weight control found that patients lost 0.6–6.0 additional kilograms of weight over 2–24 weeks of treatment. The most common side effects of the amphetamine-derived anorexiants are restlessness, insomnia, dry mouth, constipation, and increased blood pressure and heart rate.
PHEN/TPM is a combination drug that contains a catecholamine releaser (phentermine) and an anticonvulsant (topiramate). Topiramate is approved by the FDA as an anticonvulsant for the treatment of epilepsy and for the prophylaxis of migraine headaches. Weight loss was identified as an unintended side effect of topiramate during clinical trials for epilepsy. The mechanism responsible for weight loss is uncertain but is thought to be mediated through the drug’s modulation of γ-aminobutyric acid receptors, inhibition of carbonic anhydrase, and antagonism of glutamate. PHEN/TPM has undergone two 1-year pivotal randomized, placebo-controlled, double-blind trials of efficacy and safety: EQUIP and CONQUER. In a third study, SEQUEL, 78% of CONQUER participants continued to receive their blinded treatment for an additional year. All participants received diet and exercise counseling. Participant numbers, eligibility, characteristics, and weight loss outcomes are displayed in Table 21-6. Intention-to-treat 1-year placebo-subtracted weight loss for the PHEN/TPM 15-mg/92-mg dose was 9.3% and 8.6%, respectively, in the EQUIP and CONQUER trials. Clinical and statistical dose-dependent improvements were seen in selected cardiovascular and metabolic outcome measurements that were related to the weight loss. The most common adverse events experienced by the drug-randomized group were paresthesias, dry mouth, constipation, dysgeusia, and insomnia. Because of an increased risk of congenital fetal oral-cleft formation from topiramate, the FDA approval of PHEN/TPM stipulated a Risk Evaluation and Mitigation Strategies requirement to educate prescribers about the need for active birth control among women of childbearing age and a contraindication for use during pregnancy.
Lorcaserin is a selective 5-HT2C receptor agonist with a functional selectivity ~15 times that of 5-HT2A receptors and 100 times that of 5-HT2B receptors. This selectivity is important, since the drug-induced valvulopathy documented with two other serotonergic agents that were removed from the market—fenfluramine and dexfenfluramine—was due to activation of the 5-HT2B receptors expressed on cardiac valvular interstitial cells. By activating the 5-HT2C receptor, lorcaserin is thought to decrease food intake through the pro-opiomelanocortin system of neurons.
Lorcaserin has undergone two randomized, placebo-controlled, double-blind trials for efficacy and safety. Participants were randomized to receive lorcaserin (10 mg bid) or placebo in the BLOOM study and to receive lorcaserin (10 mg bid or qd) or placebo in the BLOSSOM study. All participants received diet and exercise counseling. Participant numbers, eligibility, characteristics, and weight loss outcomes are displayed in Table 21-6. Overweight or obese subjects had at least one coexisting condition (hypertension, dyslipidemia, cardiovascular disease, impaired glucose tolerance, or sleep apnea)—medical conditions that are commonly seen in the office setting. Intention-to-treat 1-year placebo-subtracted weight loss was 3.6% and 3.0%, respectively, in the BLOOM and BLOSSOM trials. Echocardiography was performed at the screening visit and at scheduled time points over the course of the studies. There was no difference in the development of FDA-defined valvulopathy between drug-treated and placebo-treated participants at 1 year or 2 years. Modest statistical improvements consistent with the weight loss were seen in selected cardiovascular and metabolic outcome measurements. The most common adverse events experienced by the drug group were headache, dizziness, and nausea.
In approving both PHEN/TPM and lorcaserin, the FDA introduced a new provision with important clinical relevance: a prescription trial period to assess effectiveness. Response to both medications should be assessed after 3 months of treatment. For lorcaserin, the medication should be discontinued if the patient has not lost at least 5% of body weight by that point. For PHEN/TPM, if the patient has not lost at least 3% of body weight at 3 months, the clinician can either escalate the dose and reassess progress at 6 months or discontinue treatment entirely. Peripherally Acting Medications
Orlistat (XenicalTM) is a synthetic hydrogenated derivative of a naturally occurring lipase inhibitor, lipostatin, that is produced by the mold Streptomyces toxytricini. This drug is a potent, slowly reversible inhibitor of pancreatic, gastric, and carboxylester lipases and phospholipase A2, which are required for the hydrolysis of dietary fat into fatty acids and monoacylglycerols. Orlistat acts in the lumen of the stomach and small intestine by forming a covalent bond with the active site of these lipases. Taken at a therapeutic dose of 120 mg tid, orlistat blocks the digestion and absorption of ~30% of dietary fat. After discontinuation of the drug, fecal fat content usually returns to normal within 48–72 h.
Multiple randomized, double-blind, placebo-controlled studies have shown that, after 1 year, orlistat produces a weight loss of ~9–10%, whereas placebo recipients have a 4–6% weight loss. Because orlistat is minimally (<1%) absorbed from the gastrointestinal tract, it has no systemic side effects. The drug’s tolerability is related to the malabsorption of dietary fat and the subsequent passage of fat in the feces. Adverse gastrointestinal effects, including flatus with discharge, fecal urgency, fatty/oily stool, and increased defecation, are reported in at least 10% of orlistat-treated patients. These side effects generally are experienced early, diminish as patients control their dietary fat intake, and only infrequently cause patients to withdraw from clinical trials. When taken concomitantly, psyllium mucilloid is helpful in controlling orlistat-induced gastrointestinal side effects. Because serum concentrations of the fat-soluble vitamins D and E and β-carotene may be reduced by orlistat treatment, vitamin supplements are recommended to prevent potential deficiencies. Orlistat was approved for over-the-counter use in 2007. Antiobesity Drugs in Development
Two additional medications are currently in development. Bupropion and naltrexone (ContraveTM)—a dopamine and norepinephrine reuptake inhibitor and an opioid receptor antagonist, respectively—are theoretically combined to dampen the motivation/reinforcement that food brings (dopamine effect) and the pleasure/palatability of eating (opioid effect). In the COR-1 randomized, double-blind, placebo-controlled trial, 1742 enrolled participants, who were 18–65 years of age and had BMIs of 30–45 kg/m2, were randomized to receive naltrexone (16 mg/d) plus bupropion (360 mg/d), naltrexone (32 mg/d) plus bupropion (360 mg/d), or placebo. Mean change in body weight for the three groups was 5.0%, 6.1%, and 1.3%, respectively. The most common adverse events were nausea, headache, constipation, dizziness, vomiting, and dry mouth. However, the FDA rejected the drug in 2011 because of cardiovascular concerns and concluded that a large-scale study of the long-term cardiovascular effects of naltrexone would be needed before approval could be considered.
Liraglutide, a glucagon-like peptide 1 receptor agonist currently approved for the treatment of type 2 diabetes, has independent weight loss effects via hypothalamic neural activation causing appetite suppression. In a double-blind, placebo-controlled trial, 564 adults with BMIs of 30–40 kg/m2 were randomized to receive once-daily SC liraglutide (1.2, 1.8, 2.4, or 3.0 mg), placebo, or open-label orlistat (120 mg tid) for 1 year. The liraglutide and placebo recipients were switched to 2.4 mg of liraglutide during the second year and then to 3.0 mg for an additional year. One-year placebo-subtracted mean weight loss was 5.8 kg for liraglutide and 3.8 kg more than those on orlistat. The most common side effects were nausea, vomiting, and change in bowel habits. SURGERY
Bariatric surgery (Fig. 21-2) can be considered for patients with severe obesity (BMI, ≥40 kg/m2) or for those with moderate obesity (BMI, ≥35 kg/m2) associated with a serious medical condition. Weight loss surgeries have traditionally been classified into three categories on the basis of anatomic changes: restrictive, restrictive malabsorptive, and malabsorptive. More recently, however, the clinical benefits of bariatric surgery in achieving weight loss and alleviating metabolic comorbidities have been attributed largely to changes in the physiologic responses of gut hormones and in adipose tissue metabolism. Metabolic effects resulting from bypassing the foregut include altered responses of ghrelin, glucagon-like peptide 1, peptide YY3-36, and oxyntonodulin. Additional effects on food intake and body weight control may be attributed to changes in vagal signaling. The loss of fat mass, particularly visceral fat, is associated with multiple metabolic, adipokine, and inflammatory changes that include improved insulin sensitivity and glucose disposal; reduced free fatty acid flux; increased adiponectin levels; and decreased interleukin 6, tumor necrosis factor α, and high-sensitivity C-reactive protein levels.
Restrictive surgeries limit the amount of food the stomach can hold and slow the rate of gastric emptying. Laparoscopic adjustable gastric banding is the prototype of this category. The first banding device, the LAP-BAND, was approved for use in the United States in 2001 and the second, the REALIZE band, in 2007. In contrast to previous devices, these bands have diameters that are adjustable by way of their connection to a reservoir that is implanted under the skin. Injection of saline into the reservoir and removal of saline from the reservoir tighten and loosen the band’s internal diameter, respectively, thus changing the size of the gastric opening. The mean percentage of total body weight lost at 5 years is estimated at 20–25%. In laparoscopic sleeve gastrectomy, the stomach is restricted by stapling and dividing it vertically, removing ~80% of the greater curvature, and leaving a slim banana-shaped remnant stomach along the lesser curvature. Weight loss after this procedure is superior to that after laparoscopic adjustable gastric banding.
The three restrictive-malabsorptive bypass procedures combine the elements of gastric restriction and selective malabsorption. These procedures are Roux-en-Y gastric bypass, biliopancreatic diversion, and biliopancreatic diversion with duodenal switch (Fig. 21-2). Roux-en-Y is the most commonly undertaken and most accepted bypass procedure. It may be performed with an open incision or by laparoscopy.
These procedures generally produce a 30–35% average total body weight loss that is maintained in nearly 60% of patients at 5 years. In general, mean weight loss is greater after the combined restrictive-malabsorptive procedures than after the restrictive procedures. Significant improvement in multiple obesity-related comorbid conditions, including type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea, quality of life, and long-term cardiovascular events, has been reported. A meta-analysis of controlled clinical trials comparing bariatric surgery versus no surgery showed that surgery was associated with a reduced odds ratio (OR) risk of global mortality (OR = 0.55), cardiovascular death (OR = 0.58), and all-cause mortality (OR = 0.70).
Among the observed improvements in comorbidities, the prevention and treatment of type 2 diabetes resulting from bariatric surgery has garnered the most attention. Fifteen-year data from the Swedish Obese Subjects study demonstrated a marked reduction (i.e., by 78%) in the incidence of type 2 diabetes development among obese patients who underwent bariatric surgery. Several randomized controlled studies have shown greater weight loss and more improved glycemic control at 1 and 2 years among surgical patients than among patients receiving conventional medical therapy. A retrospective cohort study of more than 4000 adults with diabetes found that, overall, 68.2% of patients experienced an initial complete type 2 diabetes remission within 5 years after surgery. However, among these patients, one-third redeveloped type 2 diabetes within 5 years. The rapid improvement seen in diabetes after restrictive-malabsorptive procedures is thought to be due to surgery-specific, weight-independent effects on glucose homeostasis brought about by alteration of gut hormones.
The mortality rate from bariatric surgery is generally <1% but varies with the procedure, the patient’s age and comorbid conditions, and the experience of the surgical team. The most common surgical complications include stomal stenosis or marginal ulcers (occurring in 5–15% of patients) that present as prolonged nausea and vomiting after eating or inability to advance the diet to solid foods. These complications typically are treated by endoscopic balloon dilation and acid suppression therapy, respectively. For patients who undergo laparoscopic adjustable gastric banding, there are no intestinal absorptive abnormalities other than mechanical reduction in gastric size and outflow. Therefore, selective deficiencies are uncommon unless eating habits become unbalanced. In contrast, the restrictive-malabsorptive procedures carry an increased risk for micronutrient deficiencies of vitamin B12, iron, folate, calcium, and vitamin D. Patients with restrictive-malabsorptive procedures require lifelong supplementation with these micronutrients.