Maqual R. Graham and Cameron C. Lindsey
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Explain the underlying causes of overweight and obesity.
2. Identify parameters utilized to diagnose obesity and other objective information that indicates the severity of disease.
3. Identify desired therapeutic goals for patients who are overweight or obese.
4. Recommend appropriate nonpharmacologic and pharmacologic therapeutic interventions for overweight or obese patients.
5. Implement a monitoring plan that will assess both the efficacy and safety of therapy initiated.
6. Educate patients about the disease state and associated risks, appropriate lifestyle modifications, drug therapy, and surgical options necessary for effective treatment.
KEY CONCEPTS
Body mass index (BMI), waist circumference, comorbidities, and readiness to lose weight are used in the assessment of the overweight or obese patient.
Presence of comorbidities (coronary heart disease [CHD], atherosclerosis, type 2 diabetes mellitus, and sleep apnea) and cardiovascular risk factors (cigarette smoking, hypertension, elevated low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, impaired fasting glucose, family history of premature CHD, and age) requires identification and aggressive management for overall effective treatment of the overweight or obese patient.
The treatment goals for overweight and obesity are to prevent additional weight gain, reduce and maintain a lower body weight, and control related risks.
Weight loss is indicated for patients with a BMI of 25 to 29.9 kg/m2 or an elevated waist circumference with two or more comorbidities or for any patient with a BMI of 30 kg/m2 or greater.
Weight maintenance occurs following successful achievement of weight loss.
Treatment of obesity includes lifestyle changes (e.g., dietary modification, enhanced physical activity, and behavioral therapy), pharmacologic treatment, surgical intervention, or a combination of modalities.
Pharmacotherapy, in addition to lifestyle modifications, is reserved for patients with a BMI of 30 kg/m2 or greater, or a BMI of 27 kg/m2 or greater with other obesity-related risk factors.
Weight likely will be regained if lifestyle changes are not continued indefinitely.
Surgery is warranted when other treatment attempts have failed in severely obese patients (BMI of 40 kg/m2 or greater, or 35 kg/m2 or greater with other obesity-related risk factors).
Overweight and obesity are terms used to describe weight measurements greater than what is considered healthy for a given height.1 Body mass index (BMI), waist circumference, comorbidities, and readiness to lose weight are used in the assessment of the overweight or obese patient. The primary modality in defining overweight and obesity is the BMI—a measure of body fat based on height and weight that applies to both adult men and women. The BMI accurately measures body fat when compared with body weight alone.2 Several surveys were conducted to establish categories of BMI.3 BMI does not reflect distribution of body fat; therefore, the measurement of waist circumference is a more practical method to evaluate abdominal fat before and during weight-loss treatment. Abdominal fat poses a greater health risk over peripheral fat and may be an independent risk predictor when BMI is not elevated significantly.4,5 Both BMI and waist circumference should be used in the diagnosis and management of weight loss. Evaluation of the patient’s risk status involves not only calculation of the BMI and measurement of waist circumference but also determination of comorbidities or the presence of cardiovascular disease (CVD) risk factors. Presence of comorbidities (coronary heart disease [CHD], atherosclerosis, type 2 diabetes mellitus, and sleep apnea) and cardiovascular risk factors (cigarette smoking, hypertension, elevated low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, impaired fasting glucose, family history of premature CHD, and age) requires identification and aggressive management for overall effective treatment of the overweight or obese patient. Obese patients may be at very high risk for mortality if concomitant risk factors exist; therefore, high-risk patients require aggressive modification of risk factors in addition to obesity treatment.6
Patient Encounter, Part 1
A 35-year-old female presents to your clinic wanting to lose weight. She reports not following any specific diet as they have all failed in the past. She does admit to eating out frequently. This patient does not exercise as her job and her kids are too demanding. Patient does smoke ½ pack of cigarettes per day and consumes low-calorie, caffeinated and alcoholic drinks most days. Her BMI is 32 kg/m2 and her waist circumference is 38 in.
What classification of overweight and obesity is appropriate for this patient?
Does she have other risk factors that may contribute to morbidity and/or mortality?
What additional information do you need to know before creating a treatment plan for this patient?
ETIOLOGY AND EPIDEMIOLOGY
Obesity is a multifactorial, complex disease that occurs following an interaction between genotype and the environment. While the etiology is not known completely, it involves overlapping silos of social, behavioral, and cultural influence; pathophysiology; metabolism; and genetic composition.7 The majority of overweight or obese individuals are adults, but these diseases are also prevalent in children between 2 and 19 years of age. Thirty-two percent of adults 20 years of age and older are considered obese. Almost 5% meet the criteria for extreme obesity. The prevalence of obesity in men and women of various racial or ethnic origins differ. Thirty percent of non-Hispanic white adults are considered obese where approximately 37% of Mexican Americans and 45% of non-Hispanic black Americans are obese.8
Among children and adolescents, 17% are considered overweight.8 Overweight children typically mature to overweight adults, but most obese adults were not overweight as children.9 Overweight and obesity, when present in young adults, may be a better predictor of prevalence.9 Additionally, adulthood overweight and obesity contribute to an increased risk of death in the presence of hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease (CAD), stroke, sleep apnea, gallbladder disease, osteoarthritis, and certain cancers.6 Psychosocial functioning also may be hindered because obese patients may be at risk for discrimination if negatively stereotyped.6Pediatric obesity is also associated with significant health-related problems and thus is a risk factor for much of the adult morbidity and mortality discussed previously.10,11 Cardiovascular (e.g., dyslipidemia and hypertension), endocrine (e.g., hyperinsulinemia, impaired glucose tolerance, type 2 diabetes mellitus, and menstrual irregularities), and mental (e.g., low self-esteem and depression) health problems exist for obese children and adolescents.12
PATHOPHYSIOLOGY
While a correlation between body weight in parents and children exists, the specific gene or genes contributing to obesity are unknown.13 Syndromes where obesity is a major component collectively contribute very little to the incidence of obesity.14 The key factor in the development of overweight and obesity is the imbalance that occurs between energy intake and energy expenditure. The extent of obesity is determined by the length of time this imbalance has been present. Energy intake is affected by environmental influences, including social, behavioral, and cultural factors, whereas genetic composition and metabolism affect energy expenditure.15
Energy Intake
Food intake is regulated by various receptor systems. Direct stimulation of Serotonin 1A subtype (5-HT1A) and noradrenergic α2-receptors will increase food intake, whereas Serotonin 2C subtype (5-HT2C) and noradrenergic α1-or β2-receptor activation decreases food intake. Stimulation of histamine receptor subtypes 1 and 3, and dopamine receptors 1 and 2 result in lower food consumption. Recently, the cannabinoid receptor (CB1), which is a G-protein-coupled receptor in the endocannabinoid system, has been identified and associated with food intake and regulation of energy homeostasis.16–18 Inhibition of CB1 is shown to decrease the craving for food, resulting in weight loss when coupled with dietary and lifestyle modifications.19 In addition to receptor-modulated food consumption, higher levels of the protein leptin are associated with decreased food intake.20 In contrast, elevated levels of neuropeptide Y increase food intake.20
It is debatable whether obesity is related to total calorie intake or composition of macronutrients. Of the three macronutrients (i.e., carbohydrate, protein, and fat), fat has received the most attention, given its desirable texture and its ability to augment the flavor of other foods. Food high in fat promotes weight gain, in comparison with the other macronutrients, because fat is more energy-dense. When compared with carbohydrate and protein, more than twice as many calories per gram are contained in fat. In addition, fat is stored more easily by the body compared with protein and carbohydrate.21
Energy Expenditure
A person’s metabolic rate is the primary determinant of energy expenditure. The metabolic rate is enhanced following food consumption and is directly related to the amount and type.14 Physical inactivity may predispose an individual to overweight and obesity. In addition, endocrine-related disorders (e.g., hypothyroidism and Cushing syndrome) may lower the metabolic rate, further contributing to the development of overweight and obesity.
CLINICAL PRESENTATION AND DIAGNOSIS
Any interaction between a patient and a healthcare provider presents an opportunity to evaluate the patient’s height and weight. From these parameters, the BMI should be determined as well as waist circumference and the presence of comorbidities or associated risks. BMI, waist circumference, comorbidities, and readiness to lose weight are used in the assessment of the overweight or obese patient.The BMI is calculated using the measured weight in kilograms divided by the height in meters squared (kg/m2) for all adult patients regardless of gender. The BMI distribution changes with age for children just as height and weight. Percentiles specific for age and gender are used to define overweight and obesity as well as healthy and underweight (pediatrics). The BMI is classified according to Table 102–1. Waist circumference should also be determined for adult patients by placing a measuring tape at the top of the right iliac crest and proceed around the abdomen, ensuring that the tape is tight but not constricting the skin. The value is measured following normal expiration.6Table 102–2 defines high-risk waist circumference.6Measurement of waist circumference is not recommended for children and adolescents as reference values identifying risk are unavailable.22 After obtaining patient appropriate parameters, further assess the adult patient for the presence of comorbidities and cardiovascular risk factors. Presence of comorbidities (CHD, atherosclerosis, type 2 diabetes mellitus, and sleep apnea) and cardiovascular risk factors (cigarette smoking, hypertension, elevated low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, impaired fasting glucose, family history of premature CHD, and age) requires identification and aggressive management for overall effective treatment of the overweight or obese patient. A patient is at very high absolute risk if diagnosed with CHD or other atherosclerotic diseases, type 2 diabetes mellitus, or sleep apnea or if three or more of the risk factors listed in Table 102–3 are present.6 Aggressive disease management should be initiated and not limited to weight loss. If the patient is a child or adolescent and the BMI is greater than the 85th percentile, determine the patient’s risk for future obesity-related problems or presence of obesity-related medical problems such as sleep, respiratory, GI, endocrine, cardiovascular, and psychiatric disorders.22
Table 102–1 BMI Classification
Table 102–2 High-Risk Waist Circumference
Table 102–3 Risk Factors
• Cigarette smoking
• Hypertension (systolic blood pressure greater than or equal to 140 mm Hg or diastolic blood pressure greater than or equal to 90 mm Hg) or current use of blood pressure lowering medication(s)
• Low-density lipoprotein cholesterol greater than or equal to 160 mg/dL (4.14 mmol/L)
• Low-density lipoprotein cholesterol greater than or equal to 130–159 mg/dL (3.37–4.12 mmol/L) plus two additional risk factors
• High-density lipoprotein cholesterol less than 40 mg/dL (1.03 mmol/L)
• Impaired fasting glucose (fasting blood glucose 100–125 mg/dL [5.6–6.9 mmol/L])
• Family history of premature CHD (first degree male relative less than 55 years of age or first degree female relative less than 65 years of age)
• Males greater than or equal to 45
• Females greater than or equal to 55
From Refs. 6, 23, 24.
Patient Encounter, Part 2: Medical History, Physical Exam, and Diagnostic Tests
PMH: Hypertension for 3 years, currently at goal; depression
FH: Father alive and 58 years of age. Mother also alive with history of obesity and depression.
SH: Registered nurse. Drinks alcohol most days but denies any alcohol-related problems. Smokes ½ pack of cigarettes per day.
Meds: Irbesartan 150 mg once daily; hydrochlorothiazide 25 mg once daily; fluoxetine 20 mg once daily ROS: (+) Heartburn, regurgitation; (–) chest pain, nausea, vomiting, diarrhea, change in appetite, shortness of breath, or cough.
PE:
VS: BP 120/82 mm Hg, P 82 bpm, RR 16 rpm, T 98.6° F,
wt: 240 lb; ht: 64 in
Waist Circumference: 38 in.
CV: RRR; no murmurs, rubs, gallops
Abd: Obese, soft, nontender, nondistended; (+) bowel sounds
Ext: (–) Edema
Labs: All values are within normal limits.
ECG: No evidence of past ischemia.
Given this additional information, what is your assessment of this patient?
Identify your treatment goals for the patient.
What nonpharmacologic and pharmacologic alternatives are available for the patient?
TREATMENT
Desired Outcome
General management of obesity in the adult patient is directed at weight reduction, maintenance of weight loss, and prevention of weight regain. The treatment goals for overweight and obesity are to prevent additional weight gain, reduce and maintain a lower body weight, and control related risks. A 10% weight loss as derived from the patient’s current weight is the initial goal of obesity management because favorable outcomes on the negative effects of obesity have been documented.6,25 Weight loss should occur at a rate of 0.45 to 0.9 kg (1–2 lb) per week, meeting the initial goal within the first 6 months of therapy. Weight loss is indicated for patients with a BMI of 25 to 29.9 kg/m2 or an elevated waist circumference with two or more comorbidities or for any patient with a BMI of 30 kg/m2 or greater.Weight then should be maintained (minimal regain of less than 3 kg [6.6 lb] and continued reduction in waist circumference of 1.6 in. [4 cm]). If weight loss has been achieved and/or maintained for 6 months, further therapy promoting weight loss may be inconsidered. Once maximal weight loss has been attained, any therapy used to promote the weight loss must be sustained in order to prevent weight regain.6 
Weight maintenance occurs following successful achievement of weight loss.
It is desirable to achieve a goal of improved long-term physical health for a child or adolescent. A BMI below the 85th percentile is warranted, although difficult to assess in frequent or short time periods. Thus, serial weight measurements may better quantify energy balance. Goals are most likely accomplished through adaptation of lifelong healthy lifestyle habits. In doing so, weight loss or maintenance can be attained for some children. Others may need to incorporate changes that result in a negative energy balance or energy input less than energy output.22
General Approach to Treatment
Since the goals for obesity management in the adult population are multifactorial, it should be considered a chronic illness where treatment is maintained for life. Any implemented therapy promoting weight loss should focus on behavior modification directed toward both dietary restriction and increased activity in conjunction with the selective use of pharmacologic or surgical intervention. Before initiating therapy, secondary causes of obesity (e.g., hypothyroidism and Cushing syndrome) must be considered. Current treatment with medications that negatively alter weight should be determined and if present, alternative therapies should be suggested. Table 102–4 provides a list of drugs commonly associated with weight gain. If no secondary cause exists, the presence of other cardiovascular risk factors and comorbidities must be determined to guide clinical decisions. Presence of comorbidities (CHD, atherosclerosis, type 2 diabetes mellitus, and sleep apnea) and cardiovascular risk factors (cigarette smoking, hypertension, elevated low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, impaired fasting glucose, family history of premature CHD, and age) requires identification and aggressive management for overall effective treatment of the overweight or obese patient. Therapy implemented to minimize associated risk(s) may not enhance weight loss, but weight loss will positively address risk factors. Weight loss should not be initiated in pregnant or lactating patients, decompensated psychiatric patients, or patients in whom reduced caloric intake can exacerbate an acute, serious illness.6 Treatment of obesity includes lifestyle changes (dietary modification, enhanced physical activity, and behavioral therapy), pharmacologic treatment, surgical intervention, or a combination of modalities.
Four stages have been suggested for the treatment of obesity in children and adolescents. Stage 1 or Prevention Plus is the first step for overweight or obese patients and includes adherence to healthy eating and activity habits. Patients should be encourage to eat greater than or equal to five servings of fruits and vegetables daily, limit consumption of sweetened drinks, decrease television or other screen time behaviors, and increase physical activity to greater than or equal to 1 h/day. Stage 2 or Structured Weight Management incorporates Prevention Plus habits while setting specific eating and activity goals. Responsibilities include meal planning, observed physical activity or play daily for 1 hour and, documentation of energy consumption and expenditure. Comprehensive Multidisciplinary Interventions (Stage 3) is directed at increasing the intensity of healthy behaviors. To accomplish goals, the child or adolescent should work closely with the primary care provider, registered dietician, exercise specialist, and behavioral counselor. Stage 4, Tertiary Care Intervention, may be needed for the severely obese adolescents. A very low-calorie diet (LCD), medication or weight control surgery may be warranted.22 
Treatment of obesity includes lifestyle changes (dietary modification, enhanced physical activity, and behavioral therapy), pharmacologic treatment, surgical intervention, or a combination of modalities.
Table 102–4 Drugs Contributing to Weight Gain
Anticonvulsants/mood stabilizers
Carbamazepine
Gabapentin
Valproic acid
Lithium
Antidepressants
Monoamine oxidase inhibitors (phenelzine)
Presynaptic a-2 antagonist (mirtazapine)
Selective serotonin reuptake inhibitors
Tricyclics (amitriptyline, imipramine, nortryptyline)
Antidiabetics
Insulin
Meglintinides
Sulfonylureas (glyburide, glipizide)
Thiazolidinediones
Antipsychotics
Atypical (clozapine, olanzipine, risperidone, paliperidone, quetiapine)
Others
Antihistamines
Corticosteroids
Hormonal Contraceptives (depo injections)
From Refs. 26–28.
Table 102–5 Low-Calorie Step I Diet
Nonpharmacologic Therapy
Dietary
A LCD is essential for weight-loss management in overweight and obese patients. The Step-1 Diet (Table 102–5) is a LCD recommended as part of an obesity education initiative from the National Heart, Lung, and Blood Institute.6In general, the Step-1 Diet restricts daily calories to a range of 1,000 to 1,200 kcal (4,184–5,021 kJ/day) for women weighing less than 75 kg (165 lb) and 1,400 to 1,600 kcal (5,858–6,694 kJ/day) for all others. However, this daily limit should be considered after assessing a patient’s normal daily caloric intake and ensuring that the initial caloric restriction does not exceed 500 to 1,000 kcal (2,092–4,184 kJ/day). For example, a male patient who consumes 3,000 kcal (12.552 kJ/day) should not reduce his daily caloric intake to less than 2,000 kcal (8,368 kJ/day) when initially implementing a dietary program. Further reduction to the target of 1,600 kcal (6,694 kJ/day) can be attempted once the patient has reduced calories successfully as initially recommended for a period agreeable by the provider and the patient.6 Diets too restrictive in calorie reduction are successful initially but fail long-term because compliance is difficult to sustain.29 Therefore, this less aggressive approach promotes gradual weight loss and weight maintenance.
Dietary consumption should be balanced in carbohydrates, protein, and fat. Several diet plans exist that promote weight loss through strict limitation or overabundance of only one macronutrient (e.g., low-fat, low-carbohydrate, or high-protein diets); however, overall energy consumption and expenditure will determine the amount of weight alteration. Consultation with a dietician is recommended when implementing a healthy meal plan tailored to the individual’s nutritional needs.
Exercise
While diet and exercise contribute to weight loss, combining a LCD with physical activity results in greater weight loss compared with either therapy alone.25 In addition, physical activity can help to prevent weight regain and reduce related cardiovascular risks.6 Slow titration of both the amount and intensity of physical activity is recommended for most overweight and obese patients.6 A program that incorporates daily walking is a viable option for most patients (Table 102–6). Consider 10 min/day 3 days/week with a target of 30 to 45 minutes most days, if not every day.6,30 This type and amount of activity equate to a 100 to 200 kcal (418–836 kJ/day) caloric expenditure.6
Behavioral
Nonadherence with recommended lifestyle changes may result in unsuccessful weight loss for adults.6,25 Therefore, eliminating these barriers through behavior modification is necessary to gain maximal benefit from both dietary modification and exercise. Components to successful behavioral modification include, but are not limited to, the following steps:6
• Determine the patient’s readiness to lose weight and willingness to implement a weight-loss plan.
• Build and nurture the patient–provider partnership.
• Restructure cognitive abilities.
• Set achievable goals.
• Contact the patient frequently.
• Instruct the patient on the importance and technique of self-monitoring.
Table 102–6 Examples of Moderate Physical Activity
• Control stimuli that negatively affect weight loss or weight maintenance.
• Reward the patient for any amount of weight loss or avoidance of weight regain.
Targeted behaviors should be recommended to pediatric patients and their families as healthy habits help prevent excessive weight gain. These include, but are not limited to:22
• Limit the consumption of sugar-sweetened beverages.
• Meet daily fruit and vegetable requirements set forth by the U.S. Department of Agriculture.
• Limit the amount of time watching television to 2 hours or less. Other screen time activities, such as computer play, should also be limited.
• Consume a healthy breakfast daily.
• Limit the number of times the family eats at a restaurant, especially those that serve fast food.
• Parents should eat dinner with their children and limit portion size when preparing and serving a meal.
Pharmacologic Therapy
Pharmacotherapy is not recommended for individuals with a BMI of less than 27 kg/m2. If lifestyle changes do not result in weight loss after 6 months, drug therapy, in addition to a healthy lifestyle, is warranted for overweight individuals with other related risks and for obese patients.
Table 102–7 Summary of Approved Pharmacologic Weight-Loss Agents
Pharmacotherapy, in addition to lifestyle modification, is reserved for patients with a BMI of 30 kg/m2 or greater, or a BMI of 27 kg/m2 or greater with other obesity-related risk factors. Currently available pharmacologic products are classified according to their mechanism of action, which includes the suppression of appetite and the suppression of fat absorption (Table 102–7). Therapy was indicated previously for short-term use; however, as obesity-related risks resurface with weight regain, long-term treatment is recommended to minimize these sequelae. Weight likely will be regained if lifestyle changes are not continued indefinitely. Prolonged use of both fenfluramine and dexfenfluramine monotherapy, and fenfluramine and phentermine in combination (Fen-Phen) resulted in cardiac valvular disease.31 Therefore, only two drugs are currently approved for long-term use in promoting weight loss and preventing weight regain. Sibutramine (Meridia, Abbott Laboratories) was approved by the FDA in 1997, and orlistat (Xenical, Roche Pharmaceuticals) received FDA approval in 1999. Rimonabant is a new medication entity approved for use in Europe in 2006. In June of 2007, the FDA’s Endocrine and Metabolic Drugs Advisory Committee denied approval as there was significant concern for serious psychiatric adverse events, specifically depression, anxiety, psychomotor agitation, and sleep disorders.32Approximately 20 days later, Sanofi-Aventis withdrew its application for sale of rimonabant in the United States, but remains committed to working with the FDA to make the drug available.33
Sibutramine
Sibutramine and its two active metabolites (M1 and M2) exert their effect by inhibiting the reuptake of serotonin, norepinephrine, and dopamine.34 Appetite becomes suppressed because patients feel a sense of satiety.
The effect of prolonged sibutramine use on morbidity and mortality is unknown. Most studies vary in dose and length, from 1 to 30 mg/day and 3 to 12 months of use, respectively.34 Weight loss appears proportional to the dose of sibutramine used, with greater weight loss observed using higher doses of sibutramine.34 In one trial, subjects randomized to placebo lost an average of 1.4 kg compared with an average loss of 2.9 and 5 kg using a 5 and 20 mg/day dose of sibutramine, respectively.35 Two longer-term studies have documented maximal weight loss following 6 months of sibutramine therapy and sustained weight loss over 12 months of use.34 Three trials with a study duration of greater than 6 months suggest that subjects losing 4 lb within 4 weeks of sibutramine initiation are more likely to achieve long-term weight loss.34 Conversely, sibutramine may not be effective for patients who do not achieve a weight loss of 4 lb within the initial 4 weeks.
Safe pediatric use has not been established in patients younger than 16 years of age. The efficacy of sibutramine use in overweight adolescent has been evaluated in several studies, two of which provide data for longer-term use. Patients enrolled in the first randomized trial were titrated to a sibutramine dose of 15 mg/day. Six-month data revealed a weight loss greater than placebo by a mean of 4.6 kg. Subjects taking sibutramine throughout the 12-month study period lost an average of 7 kg. Two subjects in the sibutramine group discontinued therapy after experiencing an adverse effect.36
Most recently, a 12-month, randomized double blind trial enrolled and evaluated 498 adolescents aging from 12 to 16 years. Sibutramine was initiated at 10 mg daily and increased to 15 mg if a 10% weight loss was not achieved in 6 months. BMI decreased from baseline significantly in the sibutramine-treated group.37 Data from this trial was presented by the manufacturer (Abbott Laboratories) in hopes of gaining FDA approval. The FDA determined that the safety of sibutramine could not adequately be addressed resulting in continued investigational use of sibutramine in the adolescent population.38
Since an increased waist circumference is associated with increased risk for type 2 diabetes mellitus, hyperlipidemia, hypertension, and CVD, a decrease then should reduce risk. A significant dose-related reduction in waist circumference has been reported in 6-and 12-month sibutramine trials.34 Blood glucose and lipid parameters are not adversely affected, but a small rise in blood pressure and pulse has been observed in clinical trials. On average, the blood pressure increased by 1 to 3 mm Hg, and the heart rate increased by 4 to 5 bpm. Larger increases have been observed for both blood pressure and heart rate when higher doses of sibutramine were studied. Sibutramine should be used cautiously in patients with hypertension or other disease states resulting in elevated blood pressure and/or pulse. Sibutramine is not recommended for patients with a history of congestive heart failure, CVD, arrhythmias, or stroke. Blood pressure and heart rate should be measured prior to initiating sibutramine and reassessed at regular intervals. A dose reduction or discontinuation of sibutramine should be considered for patients experiencing a sustained elevation in either blood pressure or heart rate. More common adverse reactions include dry mouth, anorexia, insomnia, constipation, and headache.34
Although not evaluated systematically, drugs that exhibit their effect on the CNS may interact with sibutramine. Since sibutramine inhibits the reuptake of serotonin, use of this drug in combination with a monoamine oxidase inhibitor (MAOI) can elevate blood levels of serotonin, resulting in a serious, potentially fatal reaction known as the serotonin syndrome. This syndrome consists of a collection of symptoms that includes one or more of the following: excitement, hypomania, restlessness, loss of consciousness, confusion, disorientation, anxiety, agitation, motor weakness, myoclonus, tremor, hemiballismus, hypereflexia, ataxia, dysarthria, incoordination, hyperthermia, shivering, pupillary dilation, diaphoresis, emesis, and tachycardia. 2 weeks should elapse between discontinuation of the MAOI (or sibutramine) and initiation of sibutramine (or MAOI) to avoid this potentially serious interaction. Concomitant administration of other serotonergic drugs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine) or medications for migraine treatment (e.g., sumatriptan) and sibutramine also should be avoided to eliminate the risk of serotonin syndrome.34 Coadministration of a decongestant and sibutramine may increase blood pressure or heart rate. Cytochrome P450 (CYP450) inhibitors, including ketoconazole, erythromycin, and cimetidine, in combination with sibutramine have resulted in increased blood levels of sibutramine; however, the clinical relevance of this is unknown.34 Highly protein-bound drugs such as warfarin or phenytoin have the potential to interact with sibutramine because it too is highly protein-bound. No data exist to evaluate the extent of this interaction.34
Since no human data exist to determine its safe use in pregnant women, sibutramine is not recommended; therefore, women of childbearing potential should use effective methods of contraception while taking sibutramine. Further, sibutramine is not recommended for lactating mothers because its excretion in breast milk is likewise unknown.34
Initiate sibutramine at a dose of 10 mg once daily, preferably in the morning without regard to meals. The dose may be increased after 4 weeks to 15 mg once daily if weight-loss goals are not attained. Doses exceeding 15 mg/day are not recommended. For patients intolerant of the 10 mg/day, a dose of 5 mg once a day may be used.34
Orlistat
Orlistat promotes and maintains weight loss by acting locally in the GI tract. Orlistat is a chemically synthesized derivative of lipstatin, a natural product of Streptomyces toxitricini that inhibits pancreatic and gastric lipases, as well as triglyceride hydrolysis. As a result, undigested triglycerides are not absorbed, causing a caloric deficit and weight loss.39
Several studies have reported significant weight loss for patients receiving orlistat 120 mg three times a day compared with placebo.40,41 Weight maintenance or prevention of weight regain also has been documented with continued orlistat use.40,42 After 1 year of treatment, 57% of orlistat-treated patients lost at least 5% of their baseline weight.39 The long-term weight-loss effect on one obesity-related comorbidity was assessed in a large placebo-controlled study. In 3,000 obese patients, 21% had impaired glucose tolerance at enrollment. After 4 years, weight loss was greater and the incidence of new diabetes was lower in patients receiving orlistat.43
One study evaluated the longer-term effect of orlistat in adolescents. In a group of 12-to 16-year-old individuals, orlistat (120 mg three times daily) in combination with diet, exercise, and behavior modification resulted in a significant reduction in BMI and waist circumference when compared to placebo. In addition, orlistat-treated subjects exhibited minimal weight increase after 1 year (0.53 kg) compared with placebo-treated patients (3.14 kg). Common adverse reactions observed were fatty or oily stools, oily spotting, oily evacuation, or abdominal pain and/or flatulence with bowel movements. Soft stools, nausea, increased defecation, and fecal incontinence also were noted.44
The safety and efficacy of orlistat have not been determined beyond 4 years of use. Minimal systemic effects exist because orlistat acts locally in the GI tract. Thus, common side effects reported include oily spotting, flatus with discharge, fecal urgency, fatty/oily stools, oily evacuation, increased defecation, and fecal incontinence.39 Other adverse events include bloating, abdominal pain, dyspepsia, nausea, vomiting, diarrhea, and headache.45
Orlistat reduces the absorption of fat-soluble vitamins. Daily intake of a multivitamin containing vitamins A, D, E, and K, as well as β-carotene, is recommended. Patients should take a multivitamin daily and preferably 2 hours prior to or after the dose of orlistat.39 Since availability of vitamin K may decline in patients receiving orlistat therapy, close monitoring of coagulation status should occur with concomitant administration of warfarin.39Administration of orlistat in conjunction with cyclosporine can result in decreased cyclosporine plasma levels. To avoid this interaction, cyclosporine should be taken 2 hours preceding or following the dose of orlistat. Additionally, cyclosporine levels should be monitored more frequently.36
Pregnant or lactating women should not take orlistat because no data exist to establish safety. Orlistat is contraindicated in patients with chronic malabsorption syndrome or cholestasis.39
Initiate orlistat 120 mg three times a day with a well-balanced but reduced-caloric meal containing no more than 30% of calories from fat. Orlistat may be taken during or up to 1 hour after the meal. If a meal is missed or contains little fat, the dose of orlistat may be omitted. Doses above 360 mg/day provide no greater benefit and thus are not recommended.
Rimonabant
Rimonabant is a selective CB1 receptor antagonist that is currently under investigation in phase III trials. CB1 receptors are found in the brain, adipose tissue, the GI tract, pituitary and adrenal glands, sympathetic ganglia, heart, lungs, liver, and bladder.15,16 Food cravings are diminished following inhibition of this receptor.17
The efficacy of rimonabant was evaluated as part of the Rimonabant in Obesity (RIO) Program. Four studies (RIO-Europe, RIO-Lipids, RIO-North America, and RIO-Diabetes) compared rimonabant 5 mg and 20 mg to placebo in 6,600 patients. Treatment with rimonabant resulted in a 4.7 kg reduction in body weight. All studies observed greater weight loss in the rimonabant treatment groups when compared to placebo.46 Improvements of waist circumference, HDL cholesterol concentration, triglyceride concentration, and A1C were also demonstrated.47 Rimonabant’s impact on cardiovascular morbidity and mortality is unknown, however, when available, the results of the Comprehensive Rimonabant Evaluation Study of Clinical Endpoints (CRESCENDO) should help fill this information void.
The most frequent side effects reported with rimonabant use include nausea, diarrhea, dizziness, and insomnia.47 RIO Program patients treated with rimonabant were 1.4 times more likely to experience an adverse effect and 2.5 times more likely to cease study participation secondary to depressive mood disorders. Depression, major depression, depressed mood, and depressed symptoms comprise depressed mood disorders.46
Two other drugs with a mechanism of action similar to rimonabant are currently in Phase III trials. Taranabant is a CB1 receptor inverse agonist where CP-945598 is a CB1 receptor antagonist. Expectation for FDA approval is unknown.48
Phentermine
Phentermine decreases food intake, and hence weight, by increasing norepinephrine and dopamine release in the CNS. This drug is indicated for short-term use—no more than a few weeks—in addition to lifestyle modifications in obese patients with a BMI of 30 kg/m2 or greater, or a BMI of 27 kg/m2 or greater in the presence of other risk factors.49
A recent meta-analysis evaluated patients at doses of 15 mg and 30 mg daily. Patients were analyzed for periods of 2 to 24 weeks. The majority of patients enrolled were female, and more than 80% of the patients evaluated received adjunctive modification in lifestyle. An average weight loss of 3.6 kg (7.9 lb) was demonstrated for patients treated with phentermine compared with placebo. Although modest in amount, this value was statistically significant.45
Safety and efficacy have not been determined in pediatric patients less than 16 years of age.49
Common adverse reactions seen with phentermine use include heart palpitations, tachycardia, elevated blood pressure, stimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremor, headache, dry mouth, constipation, and diarrhea. Phentermine should be avoided in patients with unstable cardiac status, hypertension, hyperthyroidism, agitated states, or glaucoma. In combination with fenfluramine or dexfenfluramine, primary pulmonary hypertension and valvular heart disease have been reported. The risk of developing either serious adverse effect cannot be ruled out with use of phentermine alone. Since phentermine is related to the amphetamines, the potential for abuse is high; thus, this should be kept in mind when selecting this agent as an aid for weight loss.49
Phentermine use should be avoided in patients concomitantly receiving or having received an MAOI within the preceding 14 days. Combination therapy with any stimulant or MAOI has the potential for causing hypertensive crisis. Alcohol is not recommended for patients prescribed phentermine.49
Since no studies have been conducted in pregnant women, phentermine should be administered only when clearly indicated. Owing to the potential for severe adverse effects in nursing infants, a decision to stop the drug or discontinue nursing must be made.49
Phentermine is available as an immediate-release and a sustained-release product. In conjunction with a healthy lifestyle, 30 to 37.5 mg of phentermine is administered once daily, typically before breakfast or 1 to 2 hours following the morning meal. The dosage should be individualized; some patients may be managed adequately at 15 to 18.75 mg daily, whereas a dose of 18.75 mg twice daily may be used to minimize side effects, excluding insomnia. To lessen the risk of insomnia, dosing phentermine in the evening should be avoided. Timed-release preparations of phentermine are not recommended because phentermine’s half-life is approximately 20 hours.50
Diethylpropion
This sympathomimetic amine exudes similar pharmacologic activity as the amphetamines, resulting in CNS stimulation and appetite suppression. This drug is indicated for short-term use in conjunction with a reduced-calorie diet and exercise in obese patients with a BMI of 30 kg/m2 or greater following failed attempts of diet and exercise alone.51
One meta-analysis reviewed patients receiving doses of 75 mg daily during periods of 6 to 52 weeks. Similar to study characteristics for phentermine, the majority of patients enrolled were female, and all patients implemented adjunctive lifestyle modifications. The average additional weight loss observed was 3 kg (6.6 lb) compared with diet and exercise alone, resulting in a borderline statistically significant difference.45
Safety and effectiveness of diethylpropion have not been established in patients under the age of 16; therefore, its use is not recommended.51
Use of diethylpropion for a period longer than 3 months is associated with an increased risk for development of pulmonary hypertension. When used as directed, reported common CNS adverse effects included overstimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremor, headache, jitteriness, anxiety, nervousness, depression, drowsiness, malaise, mydriasis, and blurred vision. In addition, diethylpropion can decrease seizure threshold, subsequently increasing a patient’s risk for an epileptic event. Other organ systems also can adversely be affected, resulting in tachycardia, elevated blood pressure, palpitations, dry mouth, abdominal discomfort, constipation, diarrhea, nausea, vomiting, impotence or change in libido, gynecomastia, bone marrow suppression, agranulocytosis, and leukopenia. Diethylpropion is contraindicated in patients with pulmonary hypertension, advanced arteriosclerosis, severe hypertension, hyperthyroidism, agitated states, or glaucoma. Since diethylpropion is related to the amphetamines, the potential for abuse is high, and therefore, its use is contraindicated in patients with a history of substance abuse.51
As with phentermine, use of diethypropion should be avoided in patients concomitantly receiving or having received an MAOI within the preceding 14 days to prevent hypertensive crisis. Combination with other anorectic agents should be avoided.51
No adequate studies have been conducted using diethylpropion in pregnant women; therefore, the drug should be used only if the benefit outweighs potential fetal risk. Use with caution in nursing mothers because the drug is excreted in breast milk.51
Diethylpropion is available as both an immediate-release and a controlled-release product. In conjunction with a reduced-calorie diet and/or exercise, dose diethylpropion (immediate-release) 25 mg three times a day before meals or 75 mg (controlled-release) once a day, usually midmorning.51
Other Pharmacologic Therapy
Other noradrenergic agents—not approved by the FDA and subsequently not recommended for weight loss—include amphetamine salts (e.g., ephedrine and phenylpropanolamine), methamphetamine, and benzophetamine. Although the selective serotonin reuptake inhibitors (e.g., fluoxetine and sertraline) appear to promote weight loss, further study is warranted given the inconsistent results available to date. Dietary supplements containing ephedra or ephedrine alkaloids are banned from sale following the FDA’s final ruling.52 However, ephedrine is available in nonprescription and prescription formulations for the treatment of bronchospasm, nasal congestion, hypotension/shock, and cardiac arrhythmias. Herbal products lack consistency in labeling, vary in effect, and present potentially dangerous health risks. Herbal products are not recommended.
Surgical Intervention
Weight-reduction (bariatric) surgery is an option for patients whose BMIs are 40 kg/m2 or greater, or 35 kg/m2 or greater in the presence of other comorbid conditions and who have failed more conventional approaches to weight loss.6,53 Surgery is warranted when other treatment attempts have failed in severely obese patients (BMI of 40 kg/m2 or greater, or 35 kg/m2 or greater with obesity-related risk factors). There are two basic surgical techniques: (a) gastric bypass—the full partitioning of the proximal gastric segment into a jejunal loop of the intestine—whereby weight loss is induced through both malabsorption of food and limited gastric capacity, and (b) gastroplasty—incomplete partitioning at the proximal gastric segment with the placement of a gastric outlet stoma of set diameter—which promotes weight loss by limiting gastric capacity.6,53
A meta-analysis of surgical options for obesity reported that surgical treatment produces a weight loss of 20 to 30 kg (44–66 lb) that is maintained for 5 to 10 years. Additionally, favorable outcomes for comorbid conditions are observed following surgery. When evaluating the various types of surgery available, pooled data concluded that gastric bypass produces a 10 kg (22 lb) greater weight loss at 12 and 36 months than gastroplasty procedures. Complications are inherent to any surgical procedure. The more common bariatric surgery complications are respiratory problems, wound formation, wound infections, hernia development, deep venous thrombosis, and pulmonary embolism. No differences were observed in mortality rates among various surgical procedures. Postoperative weight loss is much greater when compared with pharmacologic therapies, but no comparative trials exist.54
Gastric surgery, either banding or bypass, is an alternative offered to adolescents as it results in substantial weight loss and medical health improvement. Patients with a BMI greater than or equal to 40 kg/m2and an associated medical condition or BMI greater than or equal to 50 kg/m2, at or over the age of 13 and 15 years for girls and boys respectively, display emotional and cognitive maturity, and have implemented a behavioral-based weight-loss program are candidates for surgery.22
All patients undergoing bariatric surgery should be part of an integrated program of health education, diet, exercise, and behavioral modification before and following surgery.6 Patients must understand and commit to a substantial change in eating patterns to maintain long-term weight reduction.22,54
SPECIAL POPULATION CONSIDERATION
Elderly Patients with Obesity
The majority of obese patients are 40 to 59 years of age.8 However, the prevalence of obesity in older adults is increasing; therefore, it should not be surprising that more cardiovascular risk factors are present in this group of individuals. Additionally, obesity is a major predictor of functional limitation and mobility problems in older persons. Age alone should not prejudice the clinician from treating geriatric patients, whereas the benefits of cardiovascular health and functionality should be considered. Treatments should be initiated that minimize adverse effects on bone health and nutritional status and should include dietary and activity modifications.6
OUTCOME EVALUATION
Successful management of overweight and obesity is determined by the ability the treatment plan has to: (a) prevent weight gain, (b) reduce and maintain a lower body weight, and (c) decrease the risk of obesity-related comorbidities. Since weight is necessary to calculate the BMI, it, as well as waist circumference, should be determined. Obesity management may encompass more than weight loss or maintenance in the presence of other conditions; other pertinent parameters should be assessed at baseline. The presence of hypertension, type 2 diabetes, hyperlipidemia, CAD, sleep apnea, hypothyroidism, osteoarthritis, gallbladder disease, gout, or cancer should be determined. Blood pressure and heart rate should be measured prior to implementation of any therapy. Certain laboratory parameters also should be assessed. A basic metabolic panel, liver function tests, complete blood count, fasting lipid profile, full thyroid function tests, and other laboratory studies as deemed necessary should be obtained. An electrocardiogram should be performed if recent results are unknown.6
The patient should be assessed in 2 to 4 weeks following the implementation of therapy to determine effectiveness of and intolerance to treatment. Monthly visits are encouraged during the first 3 months. More frequent follow up may be necessary in the presence of other medical conditions. Less frequent follow up occurs after 6 months of effective weight-loss therapy.6
At each follow-up visit, compliance with a healthy lifestyle should be determined, as well as measurement of physical parameters, including weight, blood pressure, and heart rate. Waist circumference should be measured intermittently. A complete assessment also would include identification of adverse drug reactions or drug interactions if weight-loss medications have been initiated.6
Patient Care and Monitoring
1. Determine if history of BMI greater than or equal to 25 kg/m2. If unavailable or BMI unknown, obtain weight, height, and waist circumference. Calculate the BMI. Assess the patient’s willingness to lose weight.
2. If the BMI is greater than 25 kg/m2 or waist circumference greater than 35 in. for females or 40 in. for male patients, determine the presence of risk factors.
3. Prevention of weight gain is recommended in all patients with a BMI greater than or equal to 25 kg/m2. Weight loss is indicated for patients with a BMI 25 to 29.9 kg/m2, or an elevated waist circumference with two or more risk factors, or for any patient with a BMI greater than or equal to 30 kg/m2.
4. Educate the patient regarding a healthy lifestyle, one that includes a balance between caloric intake and energy expenditure as well as suggest methods to modify behavior.
5. If the patient presents with a desire to lose weight, develop treatment goals and weight-loss strategies (nonpharmacologic, drug therapy, or surgical intervention) including control of associated risks.
6. Close monitoring should follow to assess weight, BMI, waist circumference, and presence of complications related to the treatment plan. If weight-loss goals are not attained, determine reasons for failure.
Once the patient has achieved the recommended weight loss, he or she then enters the weight-maintenance phase, which includes continued contact for education, guidance, and risk-factor assessment. If weight loss is not attained, further assessment is required to determine why the goals of therapy have not been met. The interaction should be directed toward determining the motivation to lose weight, balance between caloric intake and physical activity, adherence to behavioral therapy, and determination of psychological stressors present.6
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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