Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

121. Obesity

Amy Heck Sheehan, Judy T. Chen, Jack A. Yanovski, and Karim Anton Calis


KEY CONCEPTS

 Images Two clinical measures of excess body fat, regardless of sex, are the body mass index (BMI) and the waist circumference (WC). BMI and WC provide a better assessment of total body fat than weight alone and are independent predictors of obesity-related disease risk.

 Images Excessive central adiposity increases risk for development of type 2 diabetes, hypertension, and dyslipidemia.

 Images Weight loss of as little as 5% of total body weight can significantly improve blood pressure, lipid levels, and glucose tolerance in overweight and obese patients. Sustained, large weight losses (e.g., after bariatric surgery) are associated with long-term improvements in many of the complications associated with obesity and a lower risk of both myocardial infarction and death.

 Images Bariatric surgery may be considered in patients with extreme obesity with a BMI ≥ 40 kg/m2 or ≥ BMI ≥35 kg/m2 with significant comorbidities.

 Images Pharmacotherapy may be considered in patients with a BMI ≥30 kg/m2 and/or a WC ≥40 inches (≥102 cm) for men or 35 inches (89 cm) for women, or BMI of 27 to 30 kg/m2 with concurrent risk factors if 6 months of diet, exercise, and behavioral modification fail to achieve weight loss.

 Images Long-term pharmacotherapy with centrally acting appetite suppressants should be discontinued if weight loss of at least 5% is not achieved after 12 weeks of maximum-dose therapy.

 Images There is a high probability of weight regain when obesity pharmacotherapy is discontinued.

 Images The Food and Drug Administration does not regulate labeling of herbal and food supplement diet agents, and content is not guaranteed.


INTRODUCTION

It is now estimated that more than 140 million or two of every three adults are overweight or obese in the United States.1 Additionally, the number of children and adolescents who are overweight has been increasing at an alarming rate in the last 40 years,2 with one of every three adolescents currently considered overweight or obese.3 Based on the national trend, this epidemic is projected to affect about 80% of the U.S. adults by 2020, and the prevalence of overweight among children is expected to double by 2030.4 The presence of obesity and overweight is associated with a significantly increased risk for the development of many diseases (Table 121-1),517 poorer outcomes of comorbid disease states, and increased healthcare costs. Prospective cohort studies show that overall mortality parallels increases in adiposity.18,19 The evidence is strongest for middle-aged adults. In older individuals, excess body weight and adiposity increase the risk of death, but the degree of impact diminishes with age.18,19 As of 2008, it was estimated that obesity accounts for 9.1% of total medical expenditures in the United States, and the cost of treating obesity-related illnesses in adults approached national health spending of $147 billion annually.20 National initiatives to reverse the obesity epidemic have been established through prevention strategies, consensus guidelines, and best practices.2125 This chapter reviews the epidemiology, pathophysiology, and therapeutic approaches for the management of obesity. Although nonpharmacologic treatment modalities are discussed, the pharmacotherapy of obesity is highlighted, and the role of pharmacotherapy relative to the other therapeutic options is critically reviewed.

TABLE 121-1 Conditions More Prevalent Among Patients with Obesity

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EPIDEMIOLOGY

Obesity in the United States has increased in prevalence since the 1960s. The National Health and Nutrition Examination Survey (NHANES) II data (1976–1980) estimated the prevalence of obesity among adults in the United States at 15%.2 During NHANES 1999 to 2000, the prevalence increased twofold to 30.9%,2 and by 2010 obesity affected 35.9% of the adult population,1 making the prevention of obesity a public health priority.23 This is further emphasized by the continued pursuit of safe and effective long-term therapies for obesity. Existing evidence consistently suggests that children who are overweight are at least twice as likely to remain overweight as adults compared with normal-weight children.26 Furthermore, overweight or obese children and adolescents have a higher risk of premature mortality and morbidity as adults.27 Therefore, childhood and early adulthood are critical intervention periods for prevention of obesity in the future. The prevalence of obesity varies by sex among racial and ethnic minorities within the United States.2 The highest prevalence is observed among non-Hispanic black women (58.5% obese and 17.8% with extreme obesity) compared with values of 38.8% and 7.4% for non-Hispanic black men, respectively.1 This gender disparity is also associated with the level of parental education. Young black women from the lowest educated families are at greater risk of obesity compared with young black men.28 The prevalence of obesity also increases with age, reaching a maximum by the eighth decade.2 After the age of 80 years, the prevalence falls progressively for both genders. Socioeconomic status clearly affects the prevalence of obesity among non-Hispanic white adults; a strong inverse association is observed among non-Hispanic white women from lower socioeconomic classes.2 Educational achievement, which is linked to socioeconomic status, is also correlated with the fraction of people who are overweight; the prevalence of overweight is greatest in those with less than a high school education.

ETIOLOGY

Obesity occurs when there is increased energy storage resulting from an imbalance between energy intake and energy expenditure over time. The specific etiology for this imbalance in the vast majority of individuals is multifactorial, with genetic and environmental factors contributing to various degrees. In a small minority of individuals, excess weight may be attributed to an underlying medical condition or an unintended effect of a medication.

Genetic Influences

Observational studies in humans and experimental studies in animal models have demonstrated the strong role of genetics in determining both obesity and distribution of body fat. In some individuals, genetic factors are the primary determinants of obesity, whereas in others, obesity may be caused primarily by environmental factors. The genetic contribution to the actual variance in body mass index (BMI) and body fat distribution is estimated to be up to 80%.29 The increase in the prevalence of obesity that has taken place in the United States over the past 40 years is without doubt the result of alterations in our environment that readily allow obesity-promoting genotypes to cause excessive adiposity.

The role of genetic influences in the development of obesity is an area of extensive research. A number of single-gene mutations producing extreme obesity have been identified, but such mutations are rare and account for an extremely small number of the total cases of obesity.30 Some common alleles—for instance, the rs9939609 obesity-risk allele in the FTO (fat mass and obesity associated) gene that is found in almost 70% of people—increases BMI by about 2 kg/m2.31 The total number and identity of contributing genes are still being determined, as is the means by which the many potential so-called “obesity” genes interact with each other and with the environment to produce the obese phenotype.

Environmental Factors

Many of the societal changes associated with economic development over the past 40 years have been implicated as potential causes for the increase in the prevalence of obesity. These include an abundant and easily accessible food supply and the material comforts of modern life in Western civilizations, which have contributed to a reduction in physical activity.32 Advances in technology and automation have resulted in more sedentary lifestyles during both work and leisure time for most individuals. At the same time, there has been a significant increase in the availability and portion size of high-fat foods, which are aggressively marketed and are often more convenient and less expensive than healthier alternatives. This modern environment has been described by some as “obesogenic” because it is likely to result in a state of positive energy balance in many individuals (Fig. 121-1).33 Obesity has also been reported more frequently among individuals within close social networks (e.g., siblings, spouses, and friends), with a person’s risk of becoming obese increasing significantly if a friend in his or her social network is obese.34 Finally, it should be noted that cultural factors, socioeconomic status, and religious beliefs may influence eating habits and body weights.

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FIGURE 121-1 Net energy stores are determined by various inputs and outputs. Simply stated, obesity occurs when there is an imbalance between energy intake and expenditure.

Medical Conditions

Occasionally, patients present with obesity secondary to an identifiable medical condition. Conditions associated with weight gain include iatrogenic and idiopathic Cushing’s syndrome, growth hormone deficiency, insulinoma, leptin deficiency, and various psychiatric disorders, such as depression, binge-eating disorder, and schizophrenia. Hypothyroidism is often included in this list, but it mostly causes fluid retention (myxedema) and is generally not a cause of significant obesity. Genetic syndromes that have obesity as a major component are extremely rare and include Prader-Willi’s, WAGR (Wilms’ tumor, aniridia, genitourinary abnormalities or gonadoblastoma, and mental retardation), Simpson-Golabi-Behmel’s, Cohen’s, Bardet-Biedl’s, Carpenter’s, Börjeson’s, and Wilson-Turner’s syndromes. The clinician evaluating a patient for obesity needs to be aware of these potential conditions. The physical examination of obese patients always should include an assessment for secondary causes of obesity, including genetic syndromes.

Medications

An increasing number of medications are associated with unintended weight gain.35 These include several anticonvulsants (e.g., carbamazepine, gabapentin, pregabalin, and valproic acid), antidepressants (e.g., mirtazapine and tricyclic antidepressants), atypical antipsychotics (e.g., clozapine, olanzapine, quetiapine, and risperidone), conventional antipsychotics (e.g., haloperidol), and hormones (e.g., corticosteroids, insulin, and medroxyprogesterone). Although the pharmacologic mechanism responsible for weight gain is usually drug-specific, in most cases the precise mechanism is unknown.

PATHOPHYSIOLOGY

The pathophysiology of obesity involves numerous factors that regulate appetite, energy storage, and energy expenditure. Disturbance of these homeostatic functions results in an imbalance between energy intake and energy expenditure.

Appetite

Human appetite is a complex process that is the net result of many inputs within a neural network involving principally the hypothalamus, limbic system, brainstem, hippocampus, and elements of the cortex.36Within this neural network, many neurotransmitters and neuropeptides have been identified that can stimulate or inhibit the brain’s appetite network and thereby affect total caloric intake.

Biogenic Amines

The first receptor systems found to alter food intake in animals and humans were the biogenic amines. These neurotransmitters are the foundation from which the most robust pharmacologic interventions for obesity have been developed. Serotonin, also known as 5-hydroxytryptamine (5-HT), and cells known to respond to 5-HT are found throughout the central nervous system (CNS) and the periphery. Currently, two major noradrenergic receptor subtypes are recognized (α and β), each with multiple subtypes. Histamine and dopamine also demonstrate multiple receptor subtypes, but their role in the regulation of human eating behaviors and food intake is less well documented. Direct stimulation of 5-HT1A and noradrenergic α2-receptors increases food intake; the opposite occurs with 5-HT2C and noradrenergic α1- or β2-receptor activation. Table 121-2 summarizes the major effects of direct receptor stimulation, inhibition, and changes in synaptic cleft amine concentrations on food intake.

TABLE 121-2 Effects of Various Neurotransmitters, Receptors, and Peptides on Food Intake36,37

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Neuropeptides

Many neuropeptides that influence appetite exert their effects within the hypothalamus. Thus, in the last several years research has focused on the neural projection between parts of the hypothalamus and the arcuate nucleus with signals to the paraventricular nucleus. The key peptides in this projection are currently thought to be neuropeptide Y and α-melanocyte–stimulating hormone, which engages melanocortin receptors in the paraventricular nucleus. Neuropeptide Y is the most potent known stimulator of eating, and α-melanocyte–stimulating hormone action at the melanocortin 3 and 4 receptors is one of the crucial inhibitors of eating.36,37

The lateral hypothalamus has been referred to as the “hunger” center within the brain. The most prominent of these lateral hypothalamic peptides, orexin, increases food intake stimuli within the lateral hypothalamus.36 Another important neuropeptide stimulator of eating that principally originates in the lateral hypothalamus is melanocyte-concentrating hormone. Neurons in the lateral hypothalamus use orexin and melanocyte-concentrating hormone to communicate with other neurons throughout the brain and thereby affect a number of functions beyond appetite.36,37 Table 121-2 summarizes the major effects of various neuropeptides on food intake. Although hunger and satiety functions are thought to be primarily regulated by the hypothalamus, humans eat in response to a broad set of stimuli, including reward, pleasure, learning, and memory.

Peripheral Appetite–Related Signals to the Brain

Peripheral appetite signals also dramatically affect food intake. Leptin, a hormone that is secreted by adipose cells, acts on the arcuate nucleus of the hypothalamus and elsewhere in the brain to decrease appetite and increase energy expenditure.38,39 Studies conducted in leptin-deficient mice and humans revealed that exogenous leptin administration produced significant weight loss. However, recombinant leptin replacement therapy in obese humans who are not leptin deficient has not proved successful because obese humans appear to be leptin resistant. Figure 121-2 shows the peripheral link that leptin appears to provide in signaling the CNS about the status of fat cell mass. Leptin also has been found to regulate various functions outside the CNS, including insulin and glucocorticoid secretion, reproduction, and glucose transport within the small intestine.38

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FIGURE 121-2 Intrinsic hypothalamic hunger and satiety mechanisms are modified by input from fat tissue via leptin, and from the gut via ghrelin, glucagon-like peptide-1 (GLP-1), and other hormones. Additional input is derived by direct sensing of prevailing glucose and other energy signals. The hypothalamus generates signals that are integrated within brain networks, which also receive additional signals. The brain network effects change in energy balance by modifying food intake and energy expenditure.

Other peripheral signals important to the brain’s processing of appetite include several gut hormones, notably those released by the intestine in response to passage of digesting food such as glucagon-related peptide-1, oxyntomodulin, and peptide YY.40 Each of these hormonal signals suppresses eating in animals and humans. Glucagon-related peptide-1 has other effects, most importantly as an incretin, which facilitates release of insulin by pancreatic β cells in response to meal-related glucose. Ghrelin, another important gut hormone that is released from the distal stomach and duodenum, stimulates appetite.

An understanding of the relationships among the brain, its many neurotransmitters and neuropeptides, environmental stimulation of brain activities, and other hormones is still evolving. Dysfunction in any of these factors can upset the homeostatic functions regulating energy balance. Exogenous manipulation of neural signals and associated peripheral hormones may provide future pharmacotherapeutic targets for obesity management.

Energy Balance

The net balance of energy ingested relative to energy expended by an individual over time determines the degree of obesity (see Fig. 121-1). An individual’s metabolic rate is the single largest determinant of energy expenditure. Resting energy expenditure (REE) is defined as the energy expended by a person at rest under conditions of thermal neutrality. Basal metabolic rate (BMR) is defined as the REE measured soon after awakening in the morning at least 12 hours after the last meal. Metabolic rate increases after eating based on the size and composition of the meal. It reaches a maximum approximately 1 hour after the meal is consumed and returns to basal levels 4 hours after the meal. This increase in metabolic rate is known as the thermogenic effect of food. The REE measures the energy costs of the wakeful state and may include the residual thermogenic effect of a previous meal; it is thus usually higher than the metabolic rate measured during quiet sleep. Physical activity is the other major factor that affects total energy expenditure and is the most variable component.

Peripheral Storage and Thermogenesis

There are two major types of adipose tissue, white and brown. The primary function of white adipose tissue is lipid manufacture, storage, and release. Brown adipose tissue, once believed to be found only in infants, is now recognized to exist in most adults.41 It is more commonly identified in lean than obese individuals, but its importance for human obesity remains unclear. Whereas lipid storage occurs in response to insulin, lipid release is seen during periods of calorie restriction. Brown adipose tissue is notable for its ability to dissipate energy via uncoupled mitochondrial respiration.42 Both white and brown adipose tissues are highly innervated by the sympathetic nervous system, and adrenergic stimulation via β-adrenergic receptors (β1β2, and β3) is known to activate lipolysis in fat cells as well as increase energy expenditure in adipose tissue and skeletal muscle. Genetic polymorphisms have been identified in both the β2- and β3-receptor systems that are associated with obesity or excess weight gain.43 Thus, genetic susceptibility for excess weight status may in part be related to adrenergic dysfunction.

CLINICAL PRESENTATION

Although obesity is readily apparent, most obese patients seek healthcare only when obesity-associated comorbidities become problematic. A consistent and reproducible description of weight status is essential in the diagnosis and management of obesity. Evidence-based guidelines issued by many groups, notably the World Health Organization and the National Institutes of Health (NIH), have established a stratification of weight excess based on associated medical risks.44 The first increment of excess weight is termed overweight, with the term obesity reserved for the higher levels of weight excess. These levels of excess weight are defined on the basis of BMI, a measure of total body weight relative to height. Adults with a BMI of 18.5 to 24.9 are considered to have “normal” weight; the terms overweight, obese, and extreme obese are reserved for those with a BMI of 25 to 29.9, 30 to 39.9, and 40 and over, respectively. Children and adolescents ages 2 to 18 years with a BMI at the 95th percentile or above are considered obese, and those with a BMI between the 85th and 94th percentiles are considered overweight.45 Using metric units, BMI (kg/m2) is defined as weight in kilograms divided by height in meters squared (kg/m2). Using pounds and inches, BMI (kg/m2) is estimated as (Weight [lb]/Height [inches2]) × 703. Because BMI may overestimate the degree of excess body fat in some clinical situations (e.g., edematous states, extreme muscularity, muscle wasting, and short stature), the assessment of body composition in such cases often requires clinical judgment.

Images Body mass index is an acceptable measure of obesity and is the practical method of defining obesity in the clinic and epidemiologic studies; however, it does not always correspond to excess fat. There are well-established differences in the relationship between BMI and obesity-related risks among disparate racial and ethnic groups. For examples, BMI overestimates adiposity among non-Hispanic blacks and underestimates risk among Asians.4649Ideally, obesity refers to a state of excess body fat as determined by measures of adiposity. Research techniques that can accurately measure fat mass separately from the body’s fat-free mass include determination of body density using underwater body weight or air displacement plethysmography, dual-energy x-ray absorptiometry, computed tomography (CT), and magnetic resonance imaging (MRI).50 These measurement techniques are currently too expensive and time-consuming to be used routinely in the clinical setting. Furthermore, all fat is not equal in its metabolic function or danger to health. Whereas brown adipose tissue promotes energy expenditure and has a weak association with metabolic markers of insulin production, release, and resistance, visceral white adipose tissue accumulation promotes energy storage and demonstrates a strong relationship with insulin resistance.42 Central obesity reflects high levels of intraabdominal or visceral fat, and this pattern of obesity is associated with an increased propensity for the development of hypertension, dyslipidemia, type 2 diabetes, and cardiovascular disease (sometimes referred to as the “metabolic syndrome”). Thus, in addition to the absolute excess fat mass, the distribution of this fat regionally in the body has important clinical effects. Intraabdominal fat is best estimated by imaging techniques such as CT and MRI but can be approximated through measurement of the waist circumference (WC). Clinically, WC is the narrowest circumference measured in the area between the last rib and the top of the iliac crest.51 The current definition for high-risk WC is greater than 40 inches (102 cm) in men and greater than 35 inches (89 cm) in women.51 Notably, epidemiologic studies demonstrate that WC adds little in terms of risk prediction after a patient’s BMI reaches 35 kg/m2. Thus, routine determination of WC should be implemented in those with BMIs between 25 and 34.9 kg/m2.

Images Although BMI and WC are related, each measure independently predicts disease risk. Both measurements should be assessed and monitored during therapy for obesity.52 The risks for development of type 2 diabetes, hypertension, or cardiovascular disease at various stages of obesity based on BMI or WC are outlined in Table 121-3. Note that increased WC confers increased risk even in normal-weight individuals.

TABLE 121-3 Classification of Overweight and Obesity by Body Mass Index, Waist Circumference, and Associated Disease Risk

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Comorbidities

Although overall mortality rate is not increased among those classified as overweight, those who are obese have serious health risks and increased mortality rates,52 particularly adults with BMIs greater than 35 kg/m2.53 Substantial reductions in life expectancy have been predicted in adults with BMIs greater than 35 kg/m2.53 Further reduction in life span has been observed in obese individuals who are current or former smokers.53 Several disease states and conditions are more prevalent in obese patients (see Table 121-1).517 Increased body fat, increased total body weight, and a central distribution of body fat all are associated with an increased incidence of mortality, primarily as a result of cardiovascular disease. Hypertension, hyperlipidemia, insulin resistance, and glucose intolerance are all known cardiac risk factors that tend to cluster in obese individuals. Therefore, obese individuals are exposed to multiple risk factors. Some of the earliest studies from Framingham have confirmed the relationship between obesity and increased risk of stroke and coronary heart disease in both men and women.54 Blood pressure frequently is elevated in obese individuals and may in part explain the increased incidence of stroke and cardiovascular disease observed with obesity. Hypertension in lean individuals is associated with concentric cardiac hypertrophy as a consequence of an increased afterload, which increases the risk of cardiac ischemia. In contrast, eccentric dilation is observed in obesity, leading to an increased volume load. This dilated cardiomyopathy is associated with a reduction in ventricular ejection fraction and a high-output cardiac state. The combination of obesity and hypertension is associated with thickening of the ventricular wall, ischemia, and increased heart volume. This leads more rapidly to heart failure, an association that has been recognized for more than 2 decades.55,56 Alterations in pulmonary function are common in patients with obesity. Sleep apnea, which is more common in men, is a significant and costly condition that is associated with increased morbidity and mortality in obese individuals.55,56 The exact mechanism by which obesity leads to sleep apnea is unknown, but weight loss often results in significant and sometimes dramatic improvements in the condition.

Impaired glucose tolerance and Type 2 diabetes are associated with insulin resistance and obesity. As insulin response becomes impaired, the pancreatic β cells respond by increasing insulin production and release, resulting in a state of relative hyperinsulinemia. Although hyperinsulinemia is known to be associated with an increased risk of cardiovascular disease, it is not known whether the increased insulin levels contribute directly to cardiac disease or if they are a marker for the underlying defect of insulin resistance and glucose intolerance. Insulin resistance, in turn, also frequently leads to impaired lipid metabolism (increased cholesterol, increased triglycerides, and low circulating high-density lipoprotein) and hypertension. As with cardiovascular disease, central obesity is an important factor in determining the risk of developing type 2 diabetes.

Osteoarthritis in weight-bearing joints, such as the knees, may be related directly to the mechanical effects of excess body weight and the resulting forces exerted on these joint surfaces. The increase of osteoarthritis in non–weight-bearing joints, however, suggests that obesity may lead to altered cartilage, collagen, and even bone metabolism.8 Increasing evidence has suggested proinflammatory adipocytokines, such as tumor necrosis factor-α and leptin, may play an important role in the metabolic influence of overweight on osteoarthritis.57 Osteoarthritis and its symptoms, such as pain, are significant barriers to physical activity and key impediments to sustained weight loss.

Obesity affects the human reproductive system in a number of ways. Obesity is associated with earlier menarche in girls and hyperandrogenism, hirsutism, and anovulatory menstrual cycles in women. In some women, this disorder manifests as overt polycystic ovary syndrome, a condition in which insulin resistance is common.58 Weight loss therapy with an insulin sensitizer such as metformin has been shown to restore normal ovulation in some women.58 These observations suggest that insulin resistance plays a part in the causation of polycystic ovary syndrome associated with obesity.

TREATMENT

Available treatment options for the chronic management of obesity include reduced caloric intake, increased physical activity, behavioral modification, pharmacotherapy, and bariatric surgery.

Desired Outcomes

Weight management is commonly considered successful when a predefined amount of weight has been lost such that a final goal is achieved. However, desired outcomes are fully dependent on the clinical situation. The ultimate goals of treatment must be defined clearly. These goals may be absolute weight loss if obesity is present without other comorbid conditions. If improvement in blood glucose, blood cholesterol, and hypertension are primary goals, then these must be defined appropriately and may include setting target levels for low-density lipoprotein cholesterol, glycosylated hemoglobin, or blood pressure. Per current national guidelines, the recommended weight loss goal for adults is 10% of initial weight gradually over 6 months of therapy to achieve a reasonable rate of weight loss of about 1 to 2 lb (0.5–0.9 kg) per week.6 Success may also include end points of decreasing the rate of weight gain or maintaining a weight-neutral status. All too often patients expect to lose weight overnight, only to be disappointed. Thus, it is important to set a time course for the plan. A significant number of web-based resources for supporting both patient and practitioner weight management activities are available.22,23,51

General Approach to Treatment

The success of weight loss intervention has been measured most often as weight loss over a defined study period. Successful obesity treatment plans have incorporated an integrated dietary intervention, exercise, behavior modification (with or without pharmacologic therapy), and/or surgical intervention. Specific weight goals should be established that are consistent with medical needs and the patient’s personal desire. For most obese patients, a weight loss goal of 5% to 10% of initial weight is reasonable. Patients should not be allowed to attain an abnormally low body weight (i.e., less than their estimated ideal body weight).

Patients seeking help for obesity do so for many reasons, including improvement in their quality of life, a reduction in associated morbidity, and increased life expectancy. Unfortunately, numerous individuals seek therapy for obesity primarily for cosmetic purposes and often have unrealistic goals and expectations. Aggressive marketing of weight loss programs, therapies, and diets—parallel to the fashion industry’s standards of desirable body profiles—has led many individuals to set impossible goals and expectations. In some cases, these individuals will go to extreme measures to achieve weight loss. Consequently, clinicians must be careful to fully discuss the risks of therapies and to clearly define the achievable benefits and magnitude of weight loss. Obese patients should be redirected away from trying to achieve an “ideal weight” to the more reasonable goals of modest (e.g., loss of 5%–10% of body weight) but sustained, medically relevant weight loss. In practice, the goal has to be set based on many factors, including initial body weight, patient motivation and desire, presence of comorbid conditions, and age. For example, in patients with diabetes, even modest weight loss can improve glucose control and may reduce mortality rates,5962 yet in individuals with osteoarthritis, significantly more weight reduction may be required to improve symptoms. Indeed, dietary modification and exercise have been shown to ameliorate hyperglycemia, hyperlipidemia, and hypertension with weight loss of less than 5% of initial body weight. The Look AHEAD (Action for Health in Diabetes) study found that patients with diabetes who maintained weight loss with lifestyle modifications for a period of 11 years did not experience a reduced incidence of cardiovascular events, but they did have a reduced need for diabetes medications and other positive health benefits.63 These data emphasize the importance of defining end points and measures of success in any weight loss plan.

Images Weight loss interventions must be founded on lifestyle changes, such as a modification in eating practices; complemented by drug therapy, if indicated; and in some cases, surgery (Fig. 121-3). Before recommending any therapy, the clinician must evaluate the patient for the presence of secondary causes of obesity. If a secondary cause is suspected, then a more complete diagnostic workup and the initiation of appropriate therapy may be warranted. The next step in patient evaluation is to determine the presence and severity of other medical conditions that are either directly associated with obesity (e.g., diabetes) or that have an impact on therapeutic decision making (e.g., history of liver disease or cardiac arrhythmia). Appropriate laboratory tests to exclude or quantify the degree of specific conditions such as diabetes, liver dysfunction, and nephropathy should be performed as indicated by the history and physical examination. Based on the outcome of this medical evaluation, the patient should be counseled on treatment options, benefits, and risks. No matter what the treatment options are, they all require significant effort on the part of the patient to change lifestyle and comply with the management plan. If the patient is not yet ready to meet these expectations, then early counseling will reduce the chance of frustration for the patient; clinician; and in some cases, other family members. Providing basic education can lead to a significant change in motivation and desire to lose weight and improved compliance. Ultimately, lifelong therapeutic goals should consist of maintenance of reduced body weight and prevention of weight gain.

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FIGURE 121-3 Treatment algorithm. Candidates for pharmacotherapy are selected on the basis of body mass index and waist circumference criteria along with consideration of concurrent risk factors. Medication therapy is always used as an adjunct to a comprehensive weight-loss program that includes diet, exercise, and behavioral modification. CHD, coronary heart disease; DM, diabetes mellitus; HTN, hypertension; LCD, low-calorie diet; WC, waist circumference (≥40 inches [≥102 cm] for men and ≥35 inches [≥89 cm] for women).

Nonpharmacologic Therapy

Nonpharmacologic therapy, including reduced caloric intake, increased physical activity, and behavioral modification, is the mainstay of obesity management. This combination is recommended as first-line therapy in current evidence-based clinical guidelines for the treatment of overweight and obesity in adults set forth by the NIH.6

Reduced Caloric Intake

Current adult guidelines recommend reduced caloric intake through adherence to a low-calorie diet (LCD).6 The LCD should provide a daily caloric deficit of 500 to 1,000 kcal (2,093–4,486 kJ), which generally correlates to a total intake of 800 to 1,200 kcal/day (3,349–5,024 kJ/day). Severely obese individuals will require more energy, at least at the start of dietary restriction. The composition of the LCD is outlined in the Step I Diet recommended by the third report of the Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III), as shown in Table 121-4.64Adherence to the LCD has been shown to result in an average weight loss of 8% after 6 months.6

TABLE 121-4 Recommended Composition of the Step I Low-Calorie Diet

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Clinical Controversy…

Because of the popularity of diets such as the Atkins New Diet Revolution (high fat, low carbohydrate, high protein), there is extensive coverage in the media and ongoing debate in academic circles regarding the risks, benefits, and outcomes related to diets that preferentially use macronutrient extremes (i.e., high protein vs. high carbohydrate vs. low fat). However, recent information suggests that the macronutrient composition of the diet may not be as important as consistent adherence to reduced energy consumption.

Numerous diet and nutrition plans are available to aid patients in their pursuit of weight loss. Popular diets include moderate energy-deficient plans (e.g., Weight Watchers, LEARN [Lifestyle, Exercise, Attitude, Relationships, Nutrition], and Jenny Craig), vegetarian-based plans (e.g., Ornish), and low carbohydrate plans (e.g., Zone and Atkins). Short-term weight loss is significant for almost all diet plans. However, long-term weight loss and maintenance of weight loss are less promising, primarily because of difficulty with adherence. Low-carbohydrate diets have been found to achieve better weight loss than low-fat diets for the first 6 months of treatment, but similar efficacy is generally seen after 1 year.65,66 A long-term trial of more than 800 obese patients reported no significant difference in the amount of weight loss achieved with adherence to various types of reduced-calorie diets.67 Therefore, the macronutrient composition of the diet may not be as important as consistent adherence to reduced energy consumption.

Very-low-calorie diets, providing less than 800 kcal/day (3,349 kJ/day), are generally not recommended.6 Although very-low-calorie diets can often result in early weight loss, long-term results have been disappointing because it is difficult for individuals to maintain compliance.68 Additionally, very-low-calorie diets require intensive medical monitoring and should only be used in certain situations under the supervision of an experienced clinician. Regardless of the diet program, it is clear that energy consumption must be less than energy expenditure to achieve weight loss (see Fig. 121-1). The challenge is to develop a diet plan that leads to consistent adherence by the patient and sustained weight loss and maintenance.

Increased Physical Activity

Increased physical activity is an important component in achieving the state of greater energy expenditure than energy intake that is necessary to lose weight and maintain weight loss. When increased physical activity is attempted as monotherapy, only modest weight loss has been reported.69 However, when it is combined with reduced calorie intake and behavior modification, it can augment weight loss and improve obesity-related comorbidities and cardiovascular risk factors.6,69 Current adult recommendations suggest at least 150 minutes of moderate physical activity per week.70 However, 1 hour of moderate physical activity per day may be required to augment weight loss. Patients should be advised to start slowly and gradually increase intensity. All obese patients should receive a medical examination before embarking on a physical activity program.

Behavioral Modification

Behavior modification is common to almost all weight loss interventions. The primary aim is to help patients choose lifestyles that are conducive to safe and sustained weight loss. Behavioral therapy is based on principles of human learning and thus attempts to substitute desirable behaviors for learned undesirable habits using a combination of stimulus control and reinforcement. Most such programs use self-monitoring of diet and exercise both to increase patient awareness of behavior and as a tool for the clinician to determine patient compliance as well as patient motivation.24 Behavior is reinforced by techniques that include behavioral contracting, social support, self-monitoring, relapse prevention, and (in some cases) booster treatments. Behavioral contracts are written agreements jointly developed by patients and their clinicians. Components of these agreements include goals of therapy, methods to achieve these goals, and rewards for achieving these goals. Social support requires the active participation of a close friend or relative who is involved in monitoring compliance and reinforcing behavior. Relapse prevention is geared to identifying high-risk situations for relapse, such as social events, and developing strategies to overcome barriers to maintaining healthy lifestyle choices. The most effective behavioral interventions for weight loss include a combination of several components and involve multiple treatment sessions. Updated recommendations from the U.S. Preventative Services Task Force recognize that an intensive, multicomponent behavioral intervention program can result in improved glucose tolerance and reduced cardiovascular risk in obese patients.24

Bariatric Surgery

Images Consistent with the growing obesity epidemic, the demand and popularity of bariatric surgery have increased drastically over the past 2 decades. Between 1990 and 2000, the annual prevalence of bariatric procedures grew nearly sixfold, from 2.4 to 14.1 per 100,000 adults.71 Each year, there are approximately 344,000 bariatric procedures performed worldwide.72 From 2004 to 2007, an increase of 148% in laparoscopic bariatric surgical procedures has been observed, and this number continues to rise.73


Clinical Controversy…

Current practice guidelines state that bariatric surgery may be considered in patients with a BMI of 40 kg/m2 or above or BMI of 35 kg/m2 with significant comorbidities. Although the popularity of bariatric surgery has increased drastically over the past couple decades, the long-term outcomes on the duration of comorbidity remission remain uncertain with the procedure. Researchers are also beginning to study the effects of bariatric procedures among patients with BMIs below 35 kg/m2 for remediation of comorbid conditions such as diabetes, but the long-term benefits and cost effectiveness of this approach remain unclear.

The American Association of Clinical Endocrinologists, the Obesity Society, and the American Society for Metabolic and Bariatric Surgery issued clinical practice guidelines for the perioperative management of bariatric surgical patients.74 Surgery remains the most effective intervention for the treatment of obesity. However, because of its related morbidity and mortality, this intervention is reserved for patients with extreme obesity (BMI greater than or equal to 40 kg/m2) or BMI greater than 35 kg/m2 with significant comorbidities.6,74,75 Surgical weight loss options should only be considered in patients who have met the eligibility criteria and have failed other recommended methods for weight loss. It is critical for bariatric surgical candidates to fully understand the associated surgical risks and be able to adhere to the extensive postoperative care, follow-ups, and necessary lifelong dietary and lifestyle adjustments to ensure the long-term success of the procedure. Careful patient selection and choice of procedure are critical to achieving a successful outcome. The input of an experienced surgeon working with a multidisciplinary team is invaluable in the care of these patients.

All bariatric surgical procedures achieve weight loss and maintenance through two principle mechanisms: (a) restriction or reduction of food intake by reducing stomach volume or (b) malabsorption by reducing the absorptive surface of the alimentary tract. Currently, the four major types of procedures are adjustable gastric banding, vertical banded gastroplasty, biliopancreatic diversion with duodenal switch, and conventional Roux-en-Y gastric bypass. Gastroplasty and adjustable gastric banding are designed to reduce the volume of the stomach and thus restrict the rate of nutrient intake. The biliopancreatic diversion with duodenal switch is primarily malabsorptive in nature, and the length of the diversion determines the extent of nutrient malabsorption. The conventional roux-en-Y gastric bypass is the most common procedure currently performed in the United States. It combines a restrictive approach with a degree of malabsorption induced by excluding 90% to 95% of the stomach, the entire duodenum, and a portion of the proximal jejunum from the effective alimentary tract. Conventional roux-en-Y gastric bypass yields greater and longer lasting weight loss than the other purely restrictive methods.5 Ultimately, reductions in excess body weight of about 48% to 85% can be achieved within the first 1 or 2 years, and weight loss maintenance of 25% to 68% of presurgery weight has been reported after 7 to 10 years with this procedure.5,72,74

Improvements in the peri- and postoperative care of gastric surgery patients have reduced morbidity and mortality associated with bariatric surgeries. The operative 30-day mortality rate is about 0.3% with conventional bypass or laparoscopic gastric banding76 and 1.1% with malabsorptive procedures.74 Some of the most common early complications of conventional gastric bypass are deep venous thrombosis, pulmonary emboli, anastomotic leaks, bleeding, and wound infections. Approximately one third of patients who do not receive vitamin supplementation will develop significant vitamin B12 and iron deficiency, with a large proportion demonstrating microcytic anemia.74 Empiric supplementation with one or two tablets of daily multivitamin, 1,200 to 2,000 mg/day of calcium citrate with 400 to 800 IU/day of vitamin D, 400 mcg/day of folic acid, 40 to 65 mg/day of elemental iron, and at least 350 mcg/day of oral vitamin B12 (or 500 mcg intranasally once weekly) is essential to prevent nutritional deficiencies in bariatric recipients.74 Dumping syndrome, characterized by abdominal pain and cramping, nausea, diarrhea, and bloating, tachycardia, and syncope, can occur in more than 70% of patients after roux-en-Y gastric bypass procedures74 and may complicate the provision of drug therapy in some cases. Dietary changes such as eating small, frequent meals; avoiding refined sugars; and increasing intake of fiber, complex carbohydrates, and protein can help alleviate the symptoms associated with dumping syndrome.77 Weight losses resulting from bariatric surgery are often accompanied by dramatic improvements, and sometimes complete resolution, of many obesity-related complications.78,79 With improved glycemic control and reduced insulin resistance, remission rates for type 2 diabetes mellitus have been as high as 95% after biliopancreatic diversion and 80% after gastric bypass.79,80 Such dramatic improvements of diabetes after bariatric surgery have been attributed to mechanisms that are additive to, and independent of, the weight loss effect.81 Other clinical benefits are improvements in hypertension (which may be transitory), hypertriglyceridemia, high-density lipoprotein cholesterol, cardiomyopathy, cardiac function, degenerative joint diseases, mobility, nonalcoholic fatty liver disease, respiratory functions, obstructive sleep apnea, obesity–hypoventilation syndrome, polycystic ovary syndrome, infertility, pregnancy complications, and positive psychosocial changes, as well as enhanced quality of life.78 Reduced risk of cancer-related mortality82 and cardiovascular deaths and events83 have also been documented after bariatric surgery. Furthermore, data from the prospective controlled Swedish Obese Subjects study have demonstrated a significant 29% reduction in overall mortality for patients who underwent bariatric surgery compared with those who received conventional treatments (ranging from lifestyle or behavioral modifications to no intervention) after an average follow-up duration of 10.9 years.84

After experiencing weight loss, many gastric surgery patients are able to discontinue pharmacotherapy for glucose lowering, dyslipidemia, and hypertension. Frequently, however, antihypertensive medications must be restarted after surgery even though the patient has not experienced marked weight regain. It is imperative for clinicians to recognize that bariatric interventions not only alter nutrient absorption but also may impede drug absorption.85,86Achlorhydria and reduced surface area for intestinal and gastric absorption after bariatric surgery can lead to altered dissolution of certain pH-dependent medications, such as ketoconazole, enalapril, simvastatin, tacrolimus, sirolimus, and mycophenolic acid.85,87 Furthermore, medications with narrow therapeutic windows, such as cyclosporine, thyroxine, phenytoin, and rifampin, have consistently demonstrated reduced drug absorption after bariatric surgery.86 Close therapeutic monitoring of any orally administered medication after surgery is highly recommended because dosage form selection, dose conversion, or therapeutic interchange may be necessary to avoid or minimize absorption problems and ensure bariatric surgery success.

Pharmacologic Therapy

Images The debate regarding the appropriateness of obesity pharmacotherapy remains heated, fueled by the recognized national need to treat a growing epidemic and the medical and litigious fallout from the adverse effects of dexfenfluramine (Redux) and sibutramine (Meridia). Strategies for the pharmacologic management of obesity have historically focused on modulating central or peripheral sites that regulate energy balance. Figure 121-4 depicts the sites of action of these therapies within the energy intake, storage, and expenditure cycle. Short-term use of anorexic agents is difficult to justify because of the predictable weight regain that occurs with discontinuation of therapy. Long-term pharmacotherapy may have a place in the treatment of obesity for patients who have no obvious contraindications to approved drug therapy.51,88 According to the NIH guidelines for the treatment of overweight and obese patients, pharmacotherapy may be considered in adults with BMIs of 30 kg/m2 or greater or a WC of 40 inches (102 cm) or greater for men or 35 inches (89 cm) for women or BMI of 27 to 30 kg/m2 with at least two concurrent risk factors if 6 months of diet, exercise, and behavioral modification failed to achieve weight loss.6 A pharmacotherapy treatment algorithm based on these treatment guidelines is shown in Figure 121-3Table 121-5 lists the status of the most common classes of agents currently available.

Images

FIGURE 121-4 Sites of action for obesity treatments are represented by a circled X. Most appetite suppressants act on hunger and satiety mechanisms. Traditional diets and bariatric surgery act by limiting food intake. Whereas orlistat interferes with fat absorption in the gut, gastric bypass surgery interferes with absorption more generally.

TABLE 121-5 Pharmacotherapeutic Agents for Weight Loss

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A multidisciplinary team approach to the management of obesity is necessary to ensure long-term success. It is common for patients to use a combination of nonprescription, prescription, and other complementary and alternative therapies to attain the desired weight loss goal. Therefore, clinicians should maintain a high degree of sensitivity toward the potential polypharmacy practices of patients with obesity. Finally, it is prudent to consider specific patient factors and characteristics along with the efficacy and safety profiles of individual therapies when determining if use of a pharmacologic intervention is warranted.

Agents Approved for Long-Term Use

There are currently three products approved in the United States for the chronic management of obesity. These include the lipase inhibitor orlistat (Xenical, Alli), the serotonin 2C receptor agonist lorcaserin (Belviq), and the combination product phentermine–topiramate extended release (Qsymia).


Clinical Controversy…

Obesity is considered a chronic disease. Agents currently approved by the FDA for the long-term management of obesity have limited data regarding morbidity and mortality outcomes, and the optimal treatment duration is unknown. Because discontinuation of drug treatment tends to result in weight regain, continuation of an effective and well-tolerated drug regimen is common practice.

Lipase Inhibitor: Orlistat Excessive intake of dietary fat is one of the contributing factors in the development of obesity. Gastrointestinal (GI) (gastric, pancreatic, and carboxyl ester) lipases are essential in the absorption of the long-chain triglycerides. Additionally, lipase is known to play a role in facilitating gastric emptying and secretion of other pancreaticobiliary substances. Orlistat (Xenical) is a synthetic derivative of lipstatin, a natural lipase inhibitor produced by Streptomyces toxytricini. The drug is minimally absorbed and induces weight loss by persistent lowering of dietary fat absorption through selective inhibition of the GI lipase. Furthermore, lower luminal free fatty acid concentrations result in malabsorption of cholesterol. Up to 30% reduction in fat absorption occurred with daily doses of 120 mg three times daily with meals.89 A nonprescription formulation of orlistat (Alli) is approved in the United States at a reduced daily dose of 60 mg three times daily.90 The drug must be taken within 1 hour of consuming foods that contain fat in order to exert its effect. If a meal is skipped or contains no fat, the dose of orlistat can be omitted.

Images Clinical studies using orlistat as an adjunct to diet therapy demonstrate dose-dependent reductions in fat absorption. Overall, results from clinical trials demonstrate that orlistat modestly increases the amount of weight lost and decreases the amount of weight regained during medically supervised weight loss programs.89,91 The longest trial that evaluated the safety and efficacy of orlistat is XENDOS (XENical in the prevention of Diabetes in Obese Subjects), a 4-year, double-blind, randomized, placebo-controlled prospective study.92 Although weight regain was observed with continual therapy beyond the first year of orlistat therapy, results from this study show moderate weight loss sustained after 4 years of treatment compared with placebo, 12.8 lb (5.8 kg) and 6.6 lb (3.0 kg), respectively. Weight loss using orlistat also decreased the rate of development of type 2 diabetes by 37.3% in patients with impaired glucose tolerance. Improved glycemic control can be attained in patients with type 2 diabetes by inducing or increasing weight loss with orlistat in addition to diet management.89,91 In some cases, dosages or the number of antidiabetic medications may be reduced or discontinued.89 Significant improvements in lipid profile (reduction in total and low-density lipoprotein [LDL] cholesterol), glucose control, and other markers of metabolism are seen when using orlistat in addition to the diet.89,91 Orlistat is approved for the chronic treatment of obesity in adults and adolescents ages 12 to 16 years. The recommended dose is 120 mg three times daily taken within 1 hour of consuming a fat-containing meal.

At least one GI complaint (soft stools, abdominal pain or colic, flatulence, fecal urgency, or incontinence) has been reported in up to 80% of individuals using prescription-strength orlistat. These complaints are most common in the first 1 to 2 months of therapy, are mild to moderate in severity, and tend to improve with continued orlistat use. Limiting dietary fat before initiation of orlistat therapy may be beneficial in decreasing initial GI complaints. Severe diarrhea secondary to orlistat use can affect the absorption of orally administered drugs, such as oral contraceptives, fat-soluble vitamins (A, D, E, and K) and β-carotene.89,91 Therefore, supplementation with a multivitamin should be considered during therapy. In the presence of severe diarrhea, women receiving oral contraceptives should be advised of the need to use alternative backup methods because absorption of oral contraceptive may be reduced.89Although orlistat does not appear to alter the pharmacokinetic profiles of other agents, including digoxin, glyburide, metformin, phenytoin, fluoxetine, amitriptyline, phentermine, losartan, nifedipine, captopril, atenolol, furosemide, alcohol, or atorvastatin, reduced fat absorption can potentially affect the absorption of lipophilic drugs, such as lamotrigine, valproic acid, gabapentin, and amiodarone.93 Decreased vitamin K absorption has also been noted and can alter the patient’s warfarin dosage needs.93 Clinicians should also be aware that orlistat may directly interfere with the absorption of other narrow therapeutic range drugs, such as cyclosporine and levothyroxine.93 In patients requiring concomitant therapies with orlistat, close monitoring is warranted to ensure an adequate therapeutic response. Separation of the administration times of the medications may minimize these potential drug interactions.

In 2009 to 2010, the FDA performed a complete safety review for the possible risk of a rare liver damage with the use of orlistat. Between 1999 and August 2009, there were one U.S. case with Alli and 12 foreign cases with Xenical, including two patients who died from liver failure and three who required liver transplantation, in patients using orlistat.94 Although causality has not been definitively linked to orlistat, patients are advised to monitor for any signs and symptoms of liver injury, such as development of itching, yellow eyes or skin, dark urine, loss of appetite, or light-colored stools, to their healthcare providers.

Serotonin Receptor Agonist: Lorcaserin Lorcaserin (Belviq) is a selective serotonin (5-HT2C) receptor agonist, recently approved by the FDA for chronic weight management in patients who are obese (BMI ≥30 kg/m2) or overweight (BMI >27 kg/m2) with at least one weight-related comorbidity.95 At the recommended dose of 10 mg twice daily, lorcaserin selectively activates central 5-HT2C receptors on hypothalamic anorexigenic pro-opiomelanocortin neurons. Activation of central 5-HT2C receptors results in appetite suppression, leading to reduced energy intake and enhanced satiety.

Clinical trials evaluating the efficacy of loracaserin, used in combination with a low-calorie diet and exercise counseling, have reported a modest but significantly greater weight loss compared with placebo.96,97 The Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) trial was a 2-year, randomized, placebo-controlled, double-blind, prospective trial that enrolled more than 3,000 obese and overweight patients.96Mean weight loss at 1 year was 5.8 kg (12.8 lb) in the lorcaserin group compared with 2.2 kg (4.8 lb) in the placebo group. Patients in the lorcaserin-treated group also experienced significant improvements in fasting glucose, insulin, total cholesterol, LDL cholesterol, and triglyceride concentrations at the end of the first year. Although weight regain was observed during the second year of the trial, 68% of the patients who had previously achieved 5% weight loss during the first year were able to maintain this level of weight loss by the end of the second year. The efficacy of lorcaserin has also been shown in patients with type 2 diabetes, with an average weight loss of 4.5% and significant improvements in hemoglobin A1c (HbA1c) and fasting glucose after 1 year of treatment.98 Based on data from clinical trials, the approved label states that lorcaserin therapy should be discontinued if 5% weight loss not is not achieved by week 12 because it is unlikely that a benefit will be seen.95

The most common adverse effects associated with the use of lorcaserin in clinical trials were headache, dizziness, constipation, fatigue, and dry mouth.96 Previous serotonergic agents (e.g., dexfenfluramine) used for weight loss have been associated with cardiac valvulopathy.99 The mechanism for this toxicity is thought to be related to stimulation of 5HT2B receptors on cardiac cells. At therapeutic doses, lorcaserin is selective for central 5HT2C receptors. During clinical trials, the incidence of cardiac valvulopathy was not significantly different between patients who received lorcaserin (2.4%) and those who received placebo (2%).95 However, patients should be counseled to contact their healthcare providers if they experience signs or symptoms cardiac valve disease such as dyspnea or edema. Lorcaserin should not be used in combination with other serotonergic and dopaminergic drugs because of the increased risk of serotonin syndrome or neuroleptic malignant syndrome–like reactions. Lorcaserin should be used cautiously in patients with congestive heart failure because these patients may be at an increased risk for cardiac valvulopathy. Additional rare adverse effects that clinicians should be aware of include psychiatric disorders, priapism, and elevated serum prolactin concentrations. Lorcaserin is classified as a controlled substance in class IV due to potential for abuse.

Phentermine–Topiramate Extended Release A combination product containing phentermine and topiramate extended release (Qsymia) is approved by the FDA for chronic weight management in patients who are obese (BMI ≥30 kg/m2) or overweight (BMI >27 kg/m2) with at least one weight-related comorbidity.100 Phentermine is structurally similar to amphetamine, but it has less severe CNS stimulation and a lower abuse potential. Its mechanism of action centers on its ability to enhance norepinephrine (NE) and dopamine neurotransmission, resulting in appetite suppressing effects. Topiramate is an antiepileptic drug. Although the exact mechanism for its efficacy in weight management is not known, it may decrease appetite and increase satiety through multiple pathways, including effects on γ-aminobutyrate, voltage-gated ion channels, excitatory glutamate receptors, or carbonic anhydrase.100 The doses of phentermine (3.75–15 mg) and topiramate (23–92 mg) in this combination are significantly lower than the therapeutic doses of each separate product when used as monotherapy for obesity (37.5 mg) and epilepsy (400 mg), respectively. The recommended dosing strategy for phentermine–topiramate extended release involves gradual titration, staring with 3.75 mg of phentermine and 23 mg of topiramate once daily for 14 days and then increasing the dose to 7.5 mg of phentermine and 46 mg of topiramate once daily.100 After 12 weeks of therapy, the dose may be increased again to 11.25 mg of phentermine and 69 mg of topiramate for 14 days and then to a maximum dose of 15 mg of phentermine and 92 mg of topiramate daily. Likewise, when discontinuing therapy, the dose should be gradually decreased by taking a dose every other day for at least 1 week to prevent the possible precipitation of seizures.

Clinical trials evaluating the efficacy of phentermine–topiramate, when used as an adjunct to a reduced-calorie diet and lifestyle changes, have reported dose-dependent weight loss and significant reductions in blood pressure, total cholesterol, LDL cholesterol, triglycerides, fasting glucose, and HbA1c.101,102 The CONQUER trial was a randomized, placebo-controlled, double-blind, prospective trial of 2,487 overweight or obese patients with two or more obesity-related comorbidities.101 After a 4-week dose titration phase, subjects were randomized to receive (a) placebo, (b) 7.5 mg of phentermine with 46 mg of topiramate, or (c) 15 mg of phentermine with 92 mg of topiramate daily. Weight loss at 1 year was significantly greater than placebo in both of the treatment groups, with a mean weight loss of 8.1 kg (17.8 lb) in the 7.5-mg phentermine and 46-mg topiramate group and a mean weight loss of 10.2 kg (22.4 lb) in the 15-mg phentermine and 92-mg topiramate group. The efficacy of phentermine–topiramate has also been documented in patients with class II and class III obesity (mean BMI, 42 kg/m2), with a reported mean weight loss of 10.9% after 1 year of treatment.102

The most common adverse effects associated with the use of phentermine–topiramate in clinical trials were constipation, dry mouth, paraesthesia, dysgeusia, and insomnia.101,102 Because topiramate is a known teratogen, this drug is contraindicated in pregnancy because fetal exposure in the first trimester increases the risk of cleft lip or cleft palate. To manage the potential risk of teratogenicity, the drug is only available through a limited distribution process under a risk evaluation and mitigation strategy (REMS).100 All women of childbearing age must have a documented negative pregnancy test result before beginning treatment and then monthly to continue therapy. Topiramate has been associated with acute myopia associated with secondary angle-closure glaucoma, and phentermine can cause mydriasis from adrenergic stimulation. Therefore, this product is also contraindicated in patients with glaucoma. The potential for hypertensive crisis with coadministration of phentermine and monoamine oxidase inhibitors (MAOIs) exists; therefore, patients should have stopped an MAOI for at least 14 days before use of any adrenergic agent. Phentermine–topiramate is also contraindicated in patients with untreated hyperthyroidism.

Monitoring parameters and drug interactions that clinicians should be aware of include known issues related to both components of the formulation. Of note, increases in heart rate greater than 10 beats/min were observed in approximately 50% of patients receiving phentermine–topiramate during clinical trials.100 In patients receiving the highest dose, 19% experienced increases in heart rate that were greater than 20 beats/min. Therefore, heart rate should be monitored in all patients, particularly those with preexisting cardiovascular disease. Decreases in serum bicarbonate were also noted in clinical trials, which were generally mild with peak decreases observed after 4 weeks of therapy. Decreases in serum potassium and increases in serum creatinine were also reported. Therefore, monitoring of serum electrolytes and creatinine is recommended at baseline and during therapy. Clinicians should be aware that concomitant use of non–potassium-sparing diuretics may potentiate the risk for hypokalemia. Although pregnancy risk is not expected, use of phentermine–topiramate concomitantly with oral contraceptives may result in breakthrough bleeding because of increased exposure to progestin and decreases exposure to estrogen. Phentermine–topiramate is classified as a controlled substance in schedule IV because of the abuse potential of phentermine. Similarly to lorcaserin, therapy should be discontinued if 5% weight loss is not achieved after 12 weeks.100

Images Combination Therapy Theoretically, combination therapy including any of the currently available agents would be expected to produce synergistic effects because each agent works through different mechanisms of action to induce weight loss. However, no studies are currently available evaluating the efficacy and safety of combination therapy. The concomitant use of these drugs may lead to increased adverse effects without improved therapeutic outcomes. Therefore, combination therapy is not recommended over the use of either product individually at this time.

Agents Approved for Short-Term Use

Several noradrenergic agents are currently approved by the FDA for short-term weight loss. Because short-term therapy is not consistent with current national guidelines for the chronic management of obesity, these agents have limited clinical utility in practice.

Phentermine Phentermine is available in both immediate-release and sustained-release formulations. However, the value of sustained-release formulations is questionable based on the reported phentermine plasma half-life of 12 to 24 hours.103 Phentermine is an effective adjunct to diet, exercise, and behavior modification for producing weight loss in excess of that seen with placebo.104 Intermittent phentermine therapy appears to elicit comparable weight loss as that seen with continuous use. However, most individuals experience weight regains during therapy and generally always after discontinuing use.103 A single dose of 30 mg once daily in the morning provides effective appetite suppression throughout the day. Divided doses of 8 mg immediately before meals, however, are common. Doses greater than 30 mg daily do not improve effectiveness.104 Evening or nighttime dosing should be avoided because of insomnia. Significant increases in blood pressure, palpitations, and arrhythmias can occur with phentermine administration. Use is not advisable in hypertensive patients and those with underlying cardiac abnormalities.

The potential for hypertensive crisis with coadministration of phentermine and MAOIs is noted in the product labeling of each agent; therefore, patients should be off an MAOI for at least 14 days before use of any adrenergic agent to avoid excessive adrenergic stimulation syndromes.105 Phentermine use is contraindicated in patients with hyperthyroidism or agitated states and in those who are abusers of substances such as cocaine, phencyclidine, and methamphetamine, again because of the potential for excessive adrenergic stimulation syndromes and abuse potential. Mydriasis from adrenergic stimulation can worsen glaucoma, and patients diagnosed with glaucoma should not receive phentermine. Patients with diabetes may experience altered insulin or oral hypoglycemic dosage requirements soon after beginning therapy and before any substantial weight loss. Phentermine remains the most widely prescribed weight management medication by obesity specialists despite product labeling that indicates short-term (a few weeks), monotherapy use only.106 This usage pattern deviates from the current national recommendations that promote only long-term drug intervention when obesity pharmacotherapy is appropriate.51

Diethylpropion Diethylpropion stimulates NE release from presynaptic storage granules. Increased adrenergic neurotransmitter concentrations activate hypothalamic centers, which result in decreased appetite and food intake. This drug undergoes extensive first-pass hepatic metabolism. Active metabolites are eliminated renally and account for about 70% of the administered dose. The elimination half-life of these metabolites is about 8 hours.104 Less than 10% of the parent compound is recovered in urine. No specific dosing recommendations exist for use in patients with renal or hepatic insufficiency. Diethylpropion can be taken in divided daily doses, generally 25 mg three times daily before meals. An extended-release formulation is also used by some clinicians, usually as 75 mg taken once daily in the morning or midmorning. Both dosing regimens are effective in achieving short-term weight loss in excess of placebo.107 Complaints of insomnia increase if late afternoon dosing is used. Diethylpropion causes less stimulation of the CNS than mazindol and generally causes less insomnia than phentermine. Patients with severe hypertension or significant cardiovascular disease should not receive diethylpropion. Patients with diabetes may experience decreased insulin or oral hypoglycemic dosage requirements soon after beginning therapy and before any substantial weight loss. More frequent blood glucose self-monitoring and medical follow-up are warranted when treating diabetic patients with diethylpropion.

Amphetamines Appetite suppressant effects of the amphetamines were well recognized in the 1930s. Amphetamines activate central noradrenergic receptor systems as well as dopaminergic pathways at higher doses by stimulating neurotransmitter release. Increases in blood pressure and mild bronchodilation are attributed to peripheral α- and β-receptor activation. Amphetamines are no longer widely used for the treatment of obesity because of their powerful stimulant effects and addictive potential.

Other Agents Used for Weight Management

Off-Label Use of Serotonergic Agents Serotonin is an important neurotransmitter involved in many human physiologic systems such as sleep–wake cycles, sensitivity to pain, blood pressure, mood, and eating behaviors. Increasing central serotonin levels disrupts the body’s natural development of satiety by decreasing the amount of food consumed and prolongs the time between food intake.108 Some serotonergic agents increase central serotonin concentrations via stimulating release of presynaptic stores or inhibition of reuptake into storage granules. Additionally, either the parent compound or metabolites of these agents may stimulate postsynaptic 5-HT receptors directly. Peripheral serotonin effects that have an impact on appetite, such as slowing gastric motility, have been described. A major distinction between serotonergic and noradrenergic anorexiants is that serotonergic agents lack the central stimulant effects and thus the abuse potential seen with the noradrenergic compounds.107 Conversely, decreased wakefulness, altered sleep patterns, and changes in affect can be seen. Some of the serotonergic agents were first studied as antidepressants (see Chap. 51), and when weight loss was noted in some patients, they began to be used as weight management agents. These drugs are not approved by the FDA as weight management agents and are currently not recommended for the treatment of obesity. Nonetheless, some practitioners have prescribed these agents for the treatment of obesity “off label” either alone or in combination with phentermine.

Fluoxetine is a serotonergic agent that has been prescribed as an appetite-suppressing agent. Higher doses of fluoxetine (60 mg) were generally used for weight loss as opposed to the lower doses (20 mg) frequently used for the treatment of depression. A meta-analysis of five fluoxetine trials in patients with diabetes resulted in weight loss of 4.3 kg (9.4 lb) compared with placebo over periods of up to 1 year.109Evidence also demonstrates sustained benefits in fasting blood glucose, HbA1c, and triglycerides in patients with poor glycemic control. However, weight regain was noted to occur with discontinuation of medication.

The safety and efficacy of phentermine–serotonin reuptake inhibitor combinations is limited. A case report of adverse experiences (e.g., impaired mentation, tremor, hyperreflexia, and GI symptoms) with unintentional concurrent use of phentermine and fluoxetine reinforces the need for caution by prescribers of this unapproved combination therapy.110 Although cases of pulmonary hypertension have been reported in patients exposed to fluoxetine,111 serious adverse effects such as cardiac valve abnormalities in excess of baseline prevalence have not been reported in relation to selective serotonin reuptake inhibitor use for obesity therapy.112

Noradrenergic–Serotonergic Agents Until 2010, sibutramine was available as Meridia in the United States for long-term use for weight loss. This agent induced weight loss by decreasing appetite and maintaining or increasing thermogenesis via increasing the synaptic concentration of serotonin, NE, and dopamine through reuptake inhibition. The STORM (Sibutramine Trial of Obesity Reduction and Maintenance) was the longest randomized, double-blind study to evaluate the effectiveness of sibutramine, lasting up to 2 years.113 The group receiving sibutramine achieved more weight loss than the placebo group (22.4 lb [10.2 kg] vs. 10.3 lb [4.7 kg], respectively) and had more subjects who retained at least 80% of the weight loss. Common adverse effects associated with sibutramine were increase in blood pressure and heart rate, dry mouth, anorexia, insomnia, constipation, dizziness, and nausea.91 The SCOUT (Sibutramine Cardiovascular OUTcomes) study—the first prospective trial that evaluated the potential benefits of sibutramine on cardiovascular outcomes in obese or overweight individuals with preexisting cardiovascular disease, type 2 diabetes mellitus, or both, failed to provide any reassurance regarding sibutramine’s safety.114 Although individuals taking sibutramine had modest weight loss, improvement in cardiovascular outcomes was not seen. Conversely, subjects with preexisting cardiovascular disease actually had an increased risk of nonfatal myocardial infarction and nonfatal stroke. Because of concerns that the effectiveness of sibutramine on weight loss is counterbalanced by increased rather than decreased cardiovascular risk, the drug was voluntarily withdrawn from the U.S. market.

Complementary and Alternative Therapies

Images Many complementary and alternative therapy products are currently promoted for weight loss. A nationwide survey of U.S. consumers reported that about 34% of adults reported that they had used “dietary supplements” specifically for the purposes of weight loss.115 It is important for clinicians to be aware that the regulation of dietary supplements is less rigorous than that of prescription and over-the-counter drug products. As such, a manufacturer of a dietary supplement does not have to prove the safety or effectiveness of the product before it is marketed. Of concern, some herbal and food supplement diet agents contain pharmacologically active substances that should be used with caution or avoided in obese patients with conditions such as diabetes, hypertension, and significant cardiovascular disease. In addition, many marketed products have been reported to lack consistency in labeling versus actual product content. More recently, a number of dietary supplements have been found to contain undeclared prescription drugs.116 Clinicians may access the FDA Dietary Supplement Alerts and Safety Information website to keep informed of these issues.117 Table 121-6 lists some of the common herbal and natural products used for weight loss and the constituents found in many of these products.

TABLE 121-6 Drug Monitoring

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Bitter Orange

Bitter orange (Citrus aurantium) contains m-synephrine, a sympathomimetic amine with structural similarities to ephedrine.118 After the FDA banned the sale of ephedra-containing dietary supplements in 2004, several manufacturers replaced the ephedra constituents within their products with bitter orange. Bitter orange–containing products are commonly promoted as “ephedra free.” Although bitter orange has been shown to effectively promote weight loss, it may also increase heart rate and blood pressure, potentially causing the same adverse cardiovascular effects that were observed with ephedra.118

Chromium

Chromium is considered an essential nutrient and experimentally in animals is an insulin cofactor active in carbohydrate, protein, and lipid metabolism. In humans, insulin resistance has been reported in a few cases of apparent severe chromium deficiency during long-term total parenteral nutrition (see Chap. 119). Currently, there is no reliable means of assessing total body chromium status, making diagnosis of deficiency difficult. The tryptophan metabolite, picolinic acid, forms a complex with trivalent chromium, which improves bioavailability. Food sources with highly available chromium include brewer’s yeast, calves’ liver, American cheese, and wheat germ. Clinical trials assessing chromium picolinate as a supplement to aerobic exercise in the treatment of obesity have failed to demonstrate any effectiveness.119,120

Chitosan

Chitosan is a cationic polysaccharide, specifically a partially N-deacetylated form of chitin. This nonhydrolyzable fiber exhibits properties similar to those of cellulose. In vitro and preclinical data indicate that chitosan may be effective in blocking absorption of fat from the gut. It has been suggested that orally administered chitosan may be an effective weight reduction agent by blocking calories ingested as fat. Chitosan is a major constituent in several heavily advertised weight management food supplements and nonprescription preparations. Although a small number of short-term investigations have reported that oral chitosan is more effective than placebo for weight loss, the degree of weight loss has not been clinically significant.121

Ephedra Alkaloids

Based on the known effects of ephedrine, dietary supplements claiming weight management effects have used plant sources of ephedra alkaloids. Various parts of the Ephedraceae, ma huang, Sida cordifolia, and Pinellia ternataplants are known to produce ephedra alkaloids, including L-ephedrine, D-pseudoephedrine, L-norephedrine, D-norpseudoephedrine, L-N-methylephedrine, and D-N-methylpseudoephedrine.122 Common names routinely included in dietary supplement labeling for these alkaloid sources include joint fir, popotillo, country mallow, sea grape, and yellow horse. From 1994 through July 1997, the FDA received more than 800 reports of serious adverse events; including seizures, stroke, and death, coincident with ephedrine alkaloid–containing dietary supplement use. An in-depth review of 140 reports of adverse events related to ephedrine alkaloid–containing dietary supplements demonstrated that approximately half the reports involved cardiovascular symptoms.123 In 2004, the FDA determined that all sources of ephedra alkaloids must be excluded from dietary supplements because they present an unreasonably high health risk.124

Guarana Extract and Various Tea Extracts

Guarana and tea are sources of caffeine that have inherent adrenergic properties and increase the effects of stimulant substances, such as ephedrine and ephedra alkaloids. Guarana and various tea extracts are commonly found in energy drinks and combination weight loss products that contain other substances with stimulant properties.125

Hoodia

Hoodia is a desert cactus of the Apocynaceae plant family. Natives indigenous to the Kalahari Desert are purported to consume the stems and roots of this plant for their appetite suppressant effects.126 Other names appearing on product labels are Kalahari cactus, Hoodia cactus or extract, Hoodia gordonii cactus, and Kalahari diet. Hoodia extract, sometimes referred to as P57, is rumored to elicit weight loss; however, only one short-term, randomized, placebo-controlled trial evaluating the efficacy and safety of a purified extract is available. In this 15-day study, overweight women did not experience a change in energy intake, and the purified Hoodia extract was associated with nausea, vomiting, and changes in skin sensation.127

Pyruvate

Pyruvate is a commonly listed ingredient in many herbal weight management preparations. Multiple salt forms are used, including sodium, magnesium, potassium, and calcium. Other names are α-ketopropionic acid, 2-oxypropanoic acid, and acetylformic acid. Pyruvate is a three-carbon intermediate formed during normal glucose metabolism or during glycolysis. It is advertised in the lay press for its ability to “increase metabolism” and thus promote weight loss. Objective data documenting these effects are lacking.128,129 Although most pyruvate nutritional weight management supplements contain less than 2 g per dose, large exposures (>20 g) are known to cause noticeable GI side effects, including bloating and diarrhea.

Agents Under Investigation

Several investigational pharmacologic agents are currently being evaluated for weight management. Tesofensine is a monoamine reuptake inhibitor that enhances activity of serotonin, NE, and dopamine, resulting in significant reduction in appetite.99 A randomized, double-blind, placebo-controlled, phase 2 trial of tesofensine in 203 obese patients reported dose-dependent weight loss ranging from 4.5% to 10.6% after 6 months of treatment.130

Another agent under development for obesity treatment is cetilistat, a lipase inhibitor. A randomized, double-blind, placebo-controlled trial involving 612 obese subjects with type 2 diabetes reported an average weight loss of 3.9 kg (8.5 lb) and 4.3 kg (9.5 lb) over 12 weeks in patients who received 80 mg and 120 mg, respectively, of cetilistat three times daily in combination with a hypocaloric diet.131 This trial also included an orlistat treatment arm. Orlistat-treated patients lost a similar amount of weight at 12 weeks but also reported significantly more GI adverse effects than patients who received cetilistat, suggesting that cetilistat may be better tolerated than orlistat.

After the unsuccessful use of rimonabant, a potent central and peripheral inhibitor of the cannabinoid receptor CB1 that was withdrawn from the European Union in 2008 because of serious psychiatric concerns, a selective peripheral CB1 receptor antagonist is in development.132 Although rimonabant effectively promoted weight loss, it was associated with an increased risk of serious neurologic side effects, including seizures, depression, anxiety, aggressiveness, and suicidal thoughts. These adverse effects are related to central antagonism of CB1 receptors. Development of central CB1 antagonists has been suspended, with focused research now on peripheral CB1 antagonists, to retain the weight loss efficacy reported with rimonabant, while reducing the adverse effects. Other products currently being studied for weight management include several drug combinations: bupropion and naltrexone, bupropion and zonisamide, and pramlintide and metreleptin.133

PERSONALIZED PHARMACOTHERAPY

Genetic influences are estimated to contribute to as much as 80% of the actual variance in body weight and fat distribution.29 As such, identifying specific genes involved in the development of obesity is an area of extensive research. Several gene variants have been identified over the past 15 years that are associated with the development of obesity.134 However, the use of personalized pharmacotherapy to treat obesity has only been documented in patients with congenital leptin deficiency.135 This is an extremely rare condition in which administration of recombinant human leptin results in significant improvement in body weight and other associated abnormalities of leptin deficiency. Recommendations regarding how currently available medications can be individualized to maximize patient benefit are not yet available.

EVALUATION OF THERAPEUTIC OUTCOMES

The evaluation and management of a patient with obesity requires careful clinical; biochemical; and, if necessary, psychological evaluation. This evaluation should include an assessment of the patient’s current medical condition and medication regimen. A multidisciplinary team including, but not limited to, a physician, nutritionist, psychologist, and pharmacist should be involved in the care of obese individuals.

Monitoring the Pharmaceutical Care Plan

Assessment of patient progress should be documented once or twice monthly for 1 to 2 months and then monthly thereafter.6 Each encounter should document weight, WC, BMI, blood pressure, medical history, and patient assessment of obesity medication tolerability.6 Chronic use of obesity medications should be consistent with the approved product labeling, and medication therapy should be discontinued after 3 to 4 months if the patient has failed to demonstrate weight loss or maintenance of prior weight. To achieve optimal weight loss, patients should be instructed about the importance of adherence to prescribed medication and lifestyle changes. Numerous tools for the patient and practitioner are readily available from the Department of Health and Human Services, including the National Heart Lung and Blood Institute Obesity Education Initiative.136 The Short Form 36 (SF-36) also has been used as a quality-of-life evaluation tool for obese patients undergoing programmatic weight loss. Quarterly assessments of well-being and quality of life using validated assessment tools can be helpful in objectively quantifying the effectiveness of therapy.

Patients with diabetes receiving weight loss medication require more intense medical monitoring and self-monitoring of blood glucose. Insulin therapy may need to be adjusted with the start of obesity medication therapy. Some patients with diabetes may require daily telephone contact with a healthcare provider to assist in adjusting their hypoglycemic therapy. Weekly patient visits to a healthcare setting may be necessary for 1 to 2 months until the effects of diet, exercise, and weight loss medication become more predictable. As frequent as quarterly assessment of HbA1c may be appropriate in patients with type 2 diabetes who lose weight to aid in adjustment of hypoglycemic therapy. Lipid profiles can normalize or improve with weight loss. Lipid status should be assessed semiannually or annually in patients with hyperlipidemia to determine the need for continued hyperlipidemia therapies. Weight loss also can result in normalization of blood pressure in hypertensive obese patients. Assessment of appropriateness of antihypertensive therapy should occur with each followup visit.

CONCLUSION

Obesity is a chronic disease with a prevalence that has increased dramatically over the past 30 years. Increased body weight is a consequence of increased energy storage resulting from an imbalance between energy intake and energy expenditure over time, which is influenced by many factors, including genetics and the environment. Nonpharmacologic therapy, including reduced caloric intake, increased physical activity, and behavioral modification, is currently the mainstay of obesity management. Drug therapy may be considered as an adjunct for patients who fail to achieve adequate weight loss after 6 months of diet, exercise, and behavioral modification. Currently, three products—orlistat, lorcaserin, and phentermine–topiramate extended release—are approved by the FDA for the long-term treatment of overweight and obesity. Bariatric procedures have evidence for long-term efficacy for weight reduction, but they also introduce surgical comorbidities and, for the most efficacious procedures, may cause significant nutritional deficiencies. Treatment of obesity should be individualized, considering factors such as patient desires, age, degree and duration of obesity, and the presence or absence of medical conditions both directly related to obesity and those that may have an impact on the therapeutic decisions. Regardless of the chosen treatment plan, the management of obesity is a lifelong process requiring patient support and careful monitoring for safety and efficacy.

ACKNOWLEDGMENT

This research was supported in part by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health.

ABBREVIATIONS

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