Challenging Obesity: Patient, Provider, and Expert Perspectives on the Roles of Available and Emerging Nonsurgical Therapies

Abstract

Objective

Adult obesity is recognized as a chronic disease. According to principles of chronic disease management, healthcare professionals should work collaboratively with patients to determine appropriate therapeutic strategies that address overweight and obesity, specifically considering a patient’s disease status in addition to their individual needs, preferences, and attitudes regarding treatment. A central role and responsibility of healthcare professionals in this process is to inform and educate patients about their treatment options. Although current recommendations for the management of adult obesity provide general guidance regarding safe and proper implementation of lifestyle, pharmacological, and surgical interventions, healthcare professionals need awareness of specific evidence-based information that supports individualized clinical application of these therapies. More specifically, healthcare professionals should be up-to-date on approaches that promote successful lifestyle management and be knowledgeable about newer weight loss pharmacotherapies, so they can offer patients with obesity a wide range of options to personalize their treatment. Accordingly, this educational activity has been developed to provide participants with the latest information on treatment recommendations and therapeutic advances in lifestyle intervention and pharmacotherapy for adult obesity management.

Design and Methods

This supplement is based on the content presented at a live CME symposium held in conjunction with ObesityWeek 2014.

Results

This supplement provides an expert summary of current treatment recommendations and recent advances in nonsurgical therapies for the management of adult obesity. Patient and provider perspectives on obesity management are highlighted in embedded video clips available via QR codes, and new evidence will be applied using clinically relevant case studies.

Conclusions

This supplement provides a topical update of obesity management, including clinical practice examples, for healthcare professionals who treat or provide care for adults with obesity.

Introduction

Authoritative medical organizations have classified adult obesity as a chronic disease (1–6). Consistent with the criteria that define a disease, obesity impairs normal bodily function; has characteristic signs and symptoms; and is associated with harm or morbidity, including increased risk of mortality and a wide array of complications (1–8). Obesity-associated complications can manifest as physical effects resulting from increased fat mass (e.g., osteoarthritis, obstructive sleep apnea, and urinary incontinence) or as pathological metabolic and physiologic consequences of fat tissue dysfunction and insulin resistance (e.g., cancer, dyslipidemia, hepatosteatosis, hypertension, and type 2 diabetes) (3–7,9). Obesity can also contribute to psychological disorders, including depression and social stigmatization (3). Notably, several obesity-related conditions are among the leading causes of preventable death in the United States—heart disease, stroke, type 2 diabetes, and some types of cancer (10).

Given the dire health consequences, the increasing prevalence of adult obesity in the last two to three decades (11) mandates that US healthcare providers engage in weight management as a pathway to health improvement. Estimates based on US population data from 1990 to 2008 indicate that the proportion of individuals ≥ 18 years with obesity, defined as body mass index (BMI) ≥ 30 kg/m² , more than doubled in that timeframe, increasing from 11.1% to 26.9% (11). Rates of severe obesity, defined as BMI ≥ 40 kg/m², also increased from 0.9% to 3.5% in the same period (11). More troubling, analysis of data from 2011 to 2012 revealed even higher rates of obesity (35%) and severe obesity (6%) among individuals ≥ 20 years, which is in line with projections suggesting that the prevalence of adult obesity may reach 50% by 2030 (11,12). The estimated annual US costs associated with obesity management are somewhat conflicting, however. For example, recent analysis by Finkelstein et al. (11) and Cawley and Meyerhoefer (13), respectively, attributed 9% and 21% of national health expenditures to care for individuals with obesity. Although the estimates are somewhat disparate, they are consistently high and are only expected to increase if disease prevalence trends continue (3,11,14). For these reasons, professional organizations specifically committed to obesity management have acknowledged the need for more education and training to prepare physicians and other healthcare professionals to address this growing health problem (2,3,15–17). Furthermore, there have been calls to increase the awareness and availability of resources and tools, particularly weight loss medications, so that physicians and other healthcare professionals can provide comprehensive, individualized obesity treatment (2,18,19).

To provide education and guidance regarding the comprehensive management of adult obesity, several professional groups have recently published new or updated clinical guidelines, recommendations, and/or algorithms—including a recent systematic review— dedicated to the use of pharmacotherapy for the treatment of obesity (3–6,20–23). Current recommendations address recognition of individuals who may benefit from obesity treatment, based on the presence and severity of weight-related complications (e.g., a complications-centric approach); assessment of disease severity; goals of obesity management; and identification of appropriate therapeutic options based on anticipated benefits and risks for each patient (3–6,20–23). Collaborative, chronic disease management between the patient and care provider is also emphasized to encourage individualized, patient-centered, self-managed care (3–6,21).

Fortunately, recent advances in interventions for lifestyle management and pharmacotherapy have provided clinicians with more and better options to reduce morbidity and improve quality of life for their adult patients with obesity (3). Many resources and tools have become available to help individuals with weight loss efforts, including a wide range of diet options, activity monitors, social networks, and structured weight loss programs (3,24–29). The number of pharmacotherapeutic options for the treatment of obesity has also increased, such that there are now five distinct medications approved for long-term weight management in the United States: the lipase inhibitor, orlistat; a fixed-dose combination of phentermine and topiramate; the serotonin 2c receptor agonist, lorcaserin; a fixed-dose combination of naltrexone and bupropion; and the glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, at a 3.0-mg dose (3,30).

When making recommendations to their patients about obesity management, clinicians need to be aware of the best and most recent evidence, including current treatment recommendations and new therapeutic options. Accordingly, this supplement is designed to provide physicians and other healthcare professionals with an overview of current treatment recommendations, including recognition and assessment of obesity as a disease; recent advances to promote successful lifestyle intervention; and new and emerging pharmacotherapies for obesity management. Furthermore, expert obesity medicine authors offer their insights into the specific considerations for applying treatment recommendations and therapeutic interventions in the context of clinically relevant case studies.

Expert Perspectives on the Management of Adult Obesity: Focus on Disease Recognition, Assessment, and Current Treatment Recommendations

Approaching obesity as a chronic disease: Screening to identify the need for treatment and assessing disease severity

An essential first step in treating obesity as a chronic disease is identifying individuals who may benefit from therapeutic intervention. BMI, an established measure of screening for obesity that is based on an individual’s height and weight, has been used to define body weight categories (Table 1) (5,12). On a population basis, BMI is an excellent correlate of total body fat, and numerous scientific studies have demonstrated a relationship between BMI and mortality risk (5). For instance, an analysis of 19 prospective studies including more than one million participants revealed a typical J-shaped relationship between BMI and all-cause mortality (Figure 1) (32). The lowest risk for mortality was identified for BMI levels of 22–24 kg/m² and higher risk at levels <18.5 and 25–30 kg/m² and continuously increasing risk at levels >30 kg/m² (32). A systematic review conducted toward development of the recent obesity treatment guidelines from the American Heart Association (AHA), the American College of Cardiology (ACC), and The Obesity Society (TOS) supports the BMI cut points for body weight categories presented in Table 1 (5). Additionally, the systematic review confirmed that, compared with individuals in the normal weight category (BMI 18.5–24.9 kg/m²), those with BMI > 25.0 kg/m² may have elevated risk of developing cardiovascular disease (CVD), and those with BMI ≥ 30 kg/m² may have elevated risk of mortality from all causes (5). Consequently, the guidelines confirm that current BMI cut points for overweight (>25.0–29.9 kg/m²) and obesity (≥30 kg/m²) are reasonable indicators for screening individuals who may have elevated weight-related health risks (5).

TABLE 1.

Proportion of US adults in BMI-based bodyweight categories

Weight category	BMI range (kg/m2)	Proportion of US adults (%)a
Below normal range	<18.5	31
Normal range	18.5–24.9
Overweight	25.0–29.9	34
Obese	≥30	35
Class I	30.0–34.9	21
Class II	35.0–39.9	8
Class III	≥40	6

^aBased on height and weight data for individuals ≥20 years of age from the 2011–2012 National Health and Nutrition Examination Survey (2011–2012 NHANES).

Figure 1.

Relationship between BMI and mortality risk. Analysis of 19 prospective studies with 10-year median follow-up demonstrates a J-shaped relationship between BMI and mortality risk. Studies included 1.46 million white adults, aged 19–84 years (median, 58 years; 58% women). Depicted results are for participants who reported that they had never smoked and who did not have cancer or heart disease at study baseline. (Note: smoking, cancer, and other chronic diseases produce weight loss and increase mortality, potentially confounding assessment of the relationship between BMI and mortality.) HR, hazard ratio.

Although BMI is a very good indicator of the risk of obesity-associated diseases on a population basis, it is not a perfect measure on an individual basis. Because body fat quantity and distribution can vary among individuals within given BMI ranges, it is not always accurate at predicting risk on an individual basis; there is inherent variability in the risk of weight-related complications within the different BMI categories (4,6,33). For example, in the Atherosclerosis Risk in Communities study, 70% of individuals with BMI 25–29.9 kg/m² and 40% of individuals with BMI ≥ 30 kg/m² were considered to be metabolically healthy, based on the absence of metabolic syndrome (34), and a recent systematic review and meta-analysis found that 8.9% of individuals with BMI ≥ 30 kg/m² were similarly metabolically healthy (35). The Atherosclerosis Risk in Communities study also demonstrated that metabolically healthy individuals with BMI ≥ 30 kg/m² , and to a lesser extent those with BMI 25–29.9 kg/m² , were more likely to progress to metabolic syndrome than individuals with BMI < 25 kg/ m² (hazard ratio, 4.53 and 2.73, respectively) (34). The meta-analysis also found that, among metabolically healthy individuals, the group with BMI > 30 kg/m² had an increased risk of cardiovascular (CV) events and all-cause mortality after 10 years follow-up compared with the group having BMI≥ 18 and < 25 kg/m² (relative risk, 1.24; 95% confidence interval, 1.02–1.55) (35). However, observations indicating that individuals with BMI levels above the defined normal weight range may be metabolically healthy highlight the importance of considering disease characteristics, in addition to BMI, when determining an appropriate therapeutic course of action for obesity management.

Importantly, BMI does not indicate the degree to which excess adiposity may be adversely affecting health in individual patients. Because BMI and other measurements of fat mass do not fully characterize obesity as a disease state, current treatment recommendations for adult obesity incorporate individualized disease assessment, including consideration of the risk, presence, and severity of obesity-related complications, when identifying the need for obesity treatment and when determining appropriate interventions and therapeutic intensity to achieve goals for improved health (4–6,22). Using this approach, CV risk factors and/or other obesity-related complications should be assessed in individuals with elevated BMI to help determine whether an individual would benefit from losing weight (4–6,22,36). Current treatment recommendations indicate that individuals with BMI > 25 kg/m² and one or more CV or obesity-related risk factor (including elevated waist circumference) or complication and individuals with BMI ≥ 30 kg/m², regardless of the presence of cardiometabolic risk factors, are appropriate candidates for weight loss intervention (4–6,22). The American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) have proposed a concise checklist of complications to help guide clinicians through the obesity assessment phase (Table 2) (6,22). Additionally, publications by AACE/ACE and the American Society of Bariatric Physicians (ASBP) provide comprehensive lists of complications and risk factors that may help justify the benefit of initiating weight loss therapy (6,22).

TABLE 2.

Checklist of obesity-related complications

Obesity-related complicationa	Identification based on information available in initial evaluationb
Metabolic syndrome	Waist circumference, blood pressure, triglycerides, HDL-C, fasting glucose
Prediabetes	Fasting glucosec
Type 2 diabetes	Fasting glucosec
Dyslipidemia	Fasting triglycerides and HDL-C with lipid panel
Hypertension	Systolic and diastolic sitting blood pressures
Nonalcoholic fatty liver disease	Liver examination, liver function tests
Polycystic ovary syndrome	Physical exam, review of systems
Obstructive sleep apnea	Physical exam, review of systems
Osteoarthritis	Physical exam, review of systems
Urinary stress incontinence	Physical exam, review of systems
Gastroesophageal reflux disease	Physical exam, review of systems
Disability/immobility	Physical exam, review of systems
Psychological disorder and/or stigmatization	Physical exam, review of systems
Obesity secondary to genetic syndromes, hormonal disease, iatrogenic medications	Physical exam, review of systems, review medications and supplements, family history

HDL-C, high-density lipoprotein cholesterol.

^aAdditional obesity-related complications or disease processes may be treated with weight loss.

^bInitial evaluation in patients with BMI ≥ 25 kg/m² includes: history, physical examination, review of systems, blood pressure, waist circumference, fasting glucose, fasting lipid panel, creatinine, and hepatic transaminases; further testing or evaluation may be needed to complete diagnosis and fully assess severity.

^cTwo-hour oral glucose tolerance testing may also be used to identify prediabetes or type 2 diabetes, and type 2 diabetes may also be diagnosed through glycated hemoglobin (A1C) testing.

From a primary care provider perspective, the first step is determining who needs to lose weight for health benefit. For those who are identified as candidates who may benefit from obesity treatment, the primary therapeutic goals—improved body weight and composition, health, and quality of life—are achieved principally through weight loss (3–6,21). However, the specific approach for achieving these goals can depend, at least in part, on disease severity. In the practice of medicine, it is recognized that all therapeutic interventions are associated with at least some risk of adverse effects, and the possible risks associated with a therapeutic approach need to be balanced against the risks of taking no action and the potential benefit of treatment on the patient’s health. As a general rule, more intensive interventions are associated with greater risks, and therefore, they are typically reserved for individuals with more severe disease that is more likely to result in adverse outcomes. For those individuals whose disease status poses less risk, less-intensive interventions that are associated with lower risk of adverse effects are appropriate. Thus, in addition to identifying the need for treatment, clinicians should assess disease severity to identify appropriate, individualized obesity interventions.

Accordingly, disease staging systems for obesity have been proposed to aid clinicians in diagnosing obesity and to facilitate clinical decision making. Some examples include the Edmonton Obesity Staging System (EOSS) (37) and a recently proposed framework for the diagnosis of obesity from AACE/ACE (22). Both of these systems combine anthropometric and clinical components to provide obesity diagnoses that reflect disease severity (22,37). The EOSS combines obesity class, defined by BMI (Table 1), with a staging designation (0–4) that represents severity of obesity-related risk factors or disease, physical symptoms, psychopathology, and functional limitations and/ or impairment of well-being (37). EOSS stages are graded from the absence of these comorbidities and limitations (stage 0) to severe manifestations of the same (stage 4) (37). The proposed AACE/ACE framework associates a specific diagnosis with corresponding anthropometric and clinical components, as outlined below (22):

• Overweight: BMI 25–29.9 kg/m², no obesity-related complications

• Obesity stage 0: BMI ≥ 30 kg/m², no obesity-related complications

• Obesity stage 1: BMI ≥ 25 kg/m², presence of one or more mild to moderate obesity-related complication

• Obesity stage 2: BMI ≥ 25 kg/m², presence of one or more severe obesity-related complication

For both systems, suggestions for stage-appropriate interventions increase in intensity with the obesity stage, ranging from counseling to prevent further weight gain, to aggressive management, as feasible (22,37).

Another staging system, the Cardiometabolic Disease Staging System (CMDS), employs information readily available to clinicians such as waist circumference, blood pressure, blood glucose levels, and serum lipid levels to stratify risk for development of CVD events, diabetes, and mortality (38). The Cardiometabolic Disease Staging System was developed and validated using data from large national cohort studies and the risk stages are defined as follows (38):

• Stage 0: no risk factors (metabolically healthy)

• Stage 1: one or two risk factors (i.e., high waist circumference, elevated blood pressure, reduced serum high-density lipoprotein cholesterol, and elevated fasting triglycerides)

• Stage 2: any one of metabolic syndrome, impaired fasting glucose, or impaired glucose tolerance

• Stage 3: any two of metabolic syndrome, impaired fasting glucose, or impaired glucose tolerance

• Stage 4: type 2 diabetes and/or CVD.

Stages 0 through 3, particularly, can facilitate discrimination of a wide range of cardiometabolic risk (i.e., 40-fold variability in future diabetes risk) (38).

Current treatment recommendations regarding available interventions: Balancing anticipated benefits with potential risks

Current recommendations for obesity management provide a general framework for appropriate, safe, and effective implementation of available treatment options (4–6,20,21). Although the recommendations from different groups of obesity experts are generally similar and complementary, they tend to emphasize different aspects of obesity management. The evidence-based ACC/AHA/TOS practice guidelines update the earlier National Heart, Lung, and Blood Institute guidelines and were developed, using a formal and rigorous evidence review process, to provide guidance on specific critical questions (5); the AACE/ ACE algorithm is part of a consensus statement on comprehensive diabetes treatment that was developed from the perspective of endocrinologists (4); and the ASBP algorithm was developed by obesity specialists to provide accessible, comprehensive recommendations that are updated annually and published, with supporting materials, on the organization’s website (6). Additional clinical practice guidelines are available and focus on the use of adjunct therapies in the treatment of obesity. For example, guidelines from AACE, TOS, and the American Society for Metabolic and Bariatric Surgery provide recommendations regarding the perioperative care of bariatric surgery patients, including identification of individuals who should be offered this higher risk treatment option (20). And particularly relevant, given the recent introduction of several new pharmacotherapies, are guidelines from the Endocrine Society (ES)—cosponsored by the European Society of Endocrinology (ESE) and TOS—that provide specific guidance regarding pharmacotherapy in the context of obesity management (21).

A general overview of recommendations for selection of appropriate obesity management interventions is presented in Figure 2 (4–6,20,21). Across the recommendations, comprehensive lifestyle management, including diet, exercise, and behavioral intervention, is considered the cornerstone of all weight loss treatment and is appropriate for all individuals who may benefit from obesity treatment (4–6,20,21).

Figure 2.

General recommendations regarding selection of appropriate therapeutic options for adult obesity. Lifestyle management is the core intervention for weight management and the treatment of adult obesity. Pharmacotherapy and bariatric surgery are recommended as therapies for use in addition to lifestyle management and are typically reserved for individuals at greater risk of weight-related complications or who are struggling to lose and maintain weight with lifestyle management. Some recommendations indicate that bariatric surgery may be considered for individuals with BMI ≥ 30 kg/m² who have weight-related adverse health consequences.

Specifically, the ACC/AHA/TOS guidelines provide recommendations regarding the elements of comprehensive lifestyle management (Table 3) (5). The ASBP algorithm provides similar recommendations for nutrition/diet, physical activity, and behavioral intervention (Table 3) and includes examples of ways to build more activity into one’s daily life (e.g., dancing and taking the stairs rather than the elevator) (6). The intensity of comprehensive lifestyle management can be increased by several means, including addition of more structure in the diet, more frequent office visits, and more on-site, face-to-face contact (5). Notably, low-intensity comprehensive lifestyle interventions that provide less than one treatment session per month do not consistently produce weight loss compared with usual care (e.g., provision of advice or educational materials), but moderate-intensity comprehensive lifestyle interventions that include one to two sessions per month with a trained interventionist typically produce greater mean weight losses (≈3%–5%), and high-intensity comprehensive lifestyle interventions, including ≥ 14 sessions with a trained interventionist over 6 months, have been associated with mean weight losses of ≈ 5%–10% (5). Among the available treatment options for obesity, the risk of potential harm with comprehensive lifestyle management is considered to be very low (39). More information on tools and techniques to promote successful lifestyle management is included in the section Expert Perspectives on Supporting Lifestyle Management: Constructing a Toolbox of Successful Approaches.

TABLE 3.

Elements of comprehensive lifestyle intervention

Element	Recommendations
Reduced calorie diet	Multiple methods are effective
	Set a caloric goal (1,200–1,500 kcal/day for women, 1,500–1,800 kcal/day for men, adjusted for body weight)
	Specify a caloric deficit (500 or 750 kcal/ day)
	Restrict/reduce intake of certain food types (e.g., high-carbohydrate, low-fiber, or high-fat foods) to create energy deficit
	Consider patient preferences and health status when identifying a diet-a variety of approaches can produce weight loss
Increased physical activity	Aerobic activity > 150 min/week for weight loss
	Resistance training to preserve lean mass 200–300 min/week aerobic activity to maintain weight loss
Behavioral intervention	Ideal
	Face-to-face sessions (≥14 with a trained interventionist over the first 6 months)
	Maintain efforts over 1 year
	Incorporate strategies such as goal- setting and self-monitoring
	Alternatives to face-to-face counseling
	Telephone or electronic counseling with a trained interventionist
	Commercial weight loss programs
	Tend to produce less weight loss than face-to-face counseling
	Maintenance
	Continued contact (once monthly) with a trained interventionist

Pharmacotherapy and surgery are more intensive interventions that can be used adjunct to lifestyle management. Both approaches are generally associated with greater weight loss than lifestyle management and with longer duration of weight loss maintenance. Importantly, surgery is associated with a greater risk of complications than lifestyle management, and weight loss medications can be accompanied by higher probability of adverse events. Therefore, these adjunct therapies are typically reserved for individuals at greater health risk due to obesity-associated complications and for persons who are struggling to achieve weight loss with diet and physical activity (4–6). Perspectives on the use of pharmacotherapy and bariatric surgery vary slightly across current obesity management recommendations. The ACC/AHA/TOS clinical practice guidelines and accompanying treatment algorithm generally advocate a sequential approach, recommending that individuals who have never participated in a comprehensive lifestyle management program should be encouraged to do so before considering either of these adjunct approaches (5). The recent ES/ESE/TOS guidelines on use of pharmacotherapy for the management of obesity indicate that individuals who meet specific label indications and have a history of being unable to successfully lose and maintain weight with previous attempts are likely candidates for weight loss medications (21). By comparison, the AACE/ACE and ASBP algorithms do not stipulate that a step-wise, sequential approach is strictly necessary and indicate that the aggressiveness of initial therapy should be determined by the presence and severity of weight-related complications and their adverse impact on the health of the patient (4,6). Both of these algorithms are in agreement that patients do not need to be observed in a failed attempt at lifestyle change to be candidates for medications.

Current recommendations for obesity management include the use of approved pharmacotherapies, according to their label indications, as an approach to promote greater chance of initial weight loss and long-term weight maintenance, thus leading to health improvement (4–6,21). Generally, pharmacotherapies that are approved for long-term obesity management have produced approximate mean weight losses of 5%-15% over 1 year when used in conjunction with intensive, comprehensive lifestyle intervention (30,40). As with other medications, agents approved for weight reduction have been associated with certain adverse effects and have specific warnings and precautions regarding their safe and effective use (30,40). Consistent with the prescribing information, current treatment recommendations indicate that agents approved for the long-term treatment of obesity are appropriate for individuals with BMI ≥ 27 kg/m² accompanied by one or more obesity-related risk factor or complication and for individuals with BMI > 30 kg/m² (4–6,21,30). Additional information on recently published clinical practice guidelines for obesity pharmacotherapy and on the safe and appropriate use of individual weight loss agents is presented in the section Expert Perspectives on Pharmacotherapy for Obesity Management: Focus on New Therapeutic Approaches to Meet Therapeutic Needs.

Although a comprehensive discussion of bariatric surgery is beyond the scope of this supplement, it is important to recognize that it is an appropriate treatment option for some patients. Bariatric procedures commonly used in the United States include gastric banding, Roux-en-Y gastric bypass, and sleeve gastrectomy (41). On average, weight loss with bariatric surgery is greater than with nonsurgical interventions, in the range of 15%-35%, depending on the procedure (5,42–45). Although bariatric surgery can result in greater weight loss than other interventions for obesity, it is invasive; it requires significant long-term commitment and follow-up from patients and clinicians; and patients may encounter potentially serious complications, such as leakage, obstruction, and malnutrition (5,6,20). In some cases, patients may experience variable amounts of weight regain following surgery (20), and this weight regain or complications may result in the need for revisional surgery (20). Accordingly, current treatment recommendations typically reserve bariatric surgery for individuals with more severe disease, indicated by BMI≥40 kg/m² or by BMI≥35 kg/m² with obesity-associated complications (4,5,20,21), although some recommendations also include consideration of surgical intervention for individuals with BMI ≥ 30 kg/m² for patients with compelling, weight-related adverse health consequences (6,20).

Establishing a collaborative approach to chronic obesity management: Roles and responsibilities of patients and providers in identifying nonsurgical interventions that promote individualized, patient-centered, self-managed care

Prior to deciding on an obesity management regimen for an individual, it is advisable to:

• Assess the individual’s weight loss history

• Identify drivers of weight gain and barriers to weight loss

• Consider adjustments to the patient’s lifestyle and clinical situation

• Determine weight loss expectations and set realistic goals based on the individual’s willingness to change.

It is also useful to ask the patient to describe their weight management history (weight gains and losses over time and previous weight loss attempts) and lifestyle (typical daily diet and physical activity), to ascertain whether there is a family history of diabetes, and to ask whether the patient has medical conditions that may affect weight (5). Queries such as these can help the clinician and patient develop an obesity treatment plan by addressing barriers, identifying attainable lifestyle adjustments, and making a decision regarding the use of adjunct therapies. Additionally, specific inquiries about use of medications that may affect weight are important, as they may identify opportunities to limit weight gain or promote weight loss through adjustment of existing therapeutic regimens (4–6,21). A list of medications that frequently cause weight gain, and possible alternatives that do not, is included in Table 4 (21,46).

TABLE 4.

Medication options to minimize negative impact on weight in the treatment of coexisting conditions

Category	Agents that cause weight gain		Possible alternativesa
Neuroleptics	Thioridazine, haloperidol, olanzapine, quetiapine, risperidone, clozapine, perphenazine		Ziprasidone, aripiprazole
Tricyclics (antidepressants)	Amitriptyline, nortriptyline, imipramine, doxepin, trimipramine		Bupropion,b nefazodone, fluoxetine (short term), sertraline (<1 yr)
MAOIs (antidepressants)	Phenelzine, tranylcypromine
SSRIs (antidepressants)	Fluoxetine, sertraline, paroxetine, fluvoxamine
Other (antidepressants)	Mirtazapine
Other psychiatric agents	Lithium
Anticonvulsants	Valproate, carbamazepine, gabapentin		Topiramateb, lamotrigine, zonisamideb
Antidiabetic agents	Insulin, sulfonylureas, thiazolidinediones, metiglinide		α-glucosidase inhibitors,b dipeptidyl peptidase-4 inhibitors, sodium glucose cotransporter-2 inhibitors,b glucagon-like peptide-1 receptor agonists,b metformin,b pramlintideb
Antihistamines/anticholinergics	Cyproheptadine, diphenhydramine, doxepin		Steroid inhalers, decongestants
β- and α-adrenergic blockers	Propranolol, doxazosin		ACEIs, ARBs, CCBs
Oral contraceptives	Progestational steroids		Barrier methods, intrauterine devices
Endometriosis treatment	Depot leuprolide acetate		Surgical methods
Steroid hormones	Corticosteroids, progestational steroids		NSAIDs

ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin 2 receptor antagonists; CCBs, calcium channel blockers; MAOIs, monoamine oxidase inhibitors; NSAIDs, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors.

^aSubstituting common medications that are associated with weight gain with agents that are weight neutral or that promote weight loss should be considered, if possible, to support weight control efforts.

^bAgents associated with weight loss.

Prior to developing a treatment plan, it is also essential to establish realistic weight loss expectations and goals, as some individuals may have lofty expectations and goals that could be extremely difficult to achieve. For example, in a study of 60 women with mean weight of 99.1 kg, participants identified that their “dream” weight would be 61.4 kg, representing a 38% weight loss; that their current goal was 66.5 kg, representing a 33% weight loss; and that a final weight of 81.9 kg, representing a 17% weight loss, would be disappointing (47). Importantly, patients should be aware that the evidence indicates that weight loss of 5%-10% can result in clinically significant benefits for improved health (4–6). However, because greater weight loss has been associated with greater health improvements (48–57), individuals who are interested in achieving greater weight loss goals should also be informed of the efforts required to do so.

As previously noted, the level of acceptable risk is influenced by the potential consequences of no intervention (i.e., disease severity), the anticipated benefits of the intervention, and the potential adverse consequences of the intervention. According to principles of chronic disease management, the healthcare professional and the individual receiving treatment should collaboratively identify an approach with levels of benefit and risk that are acceptable to the patient (4–6,58), because ultimately, the patient is the one who needs to be able to implement the regimen on a daily basis. For instance, patients may be encouraged by the promise of substantial weight loss associated with bariatric surgery, but they should also be aware that they will need to undergo extensive presurgical assessment, screening, education, and preparation, and adhere to long-term lifestyle changes and clinical follow-up, to achieve and maintain optimal obesity management results. For these reasons, in addition to assessing a patient’s disease status to determine appropriate interventions, the clinician should educate the patient regarding the relative risks and benefits of available treatment options; confirm that the patient understands risks, benefits, and their role in treatment; and obtain affirmation that the patient is willing to follow a given course of treatment.

As illustrated in Figure 3, better adherence to an obesity treatment plan is associated with greater weight loss (59). Therefore, each patient should work with clinicians who are coordinating their obesity management to identify a plan they can adhere to. The five A’s of obesity management can facilitate effective communication between clinicians and patients (6). According to this model, clinicians should:

• Ask

  • Ask for permission to discuss body weight
  • Explore the patient’s readiness for change
• Assess

  • Assess BMI, waist circumference, and obesity stage
  • Explore drivers and complications of excess weight
• Advise

  • Advise the patient about the health risks of obesity, the benefits of modest weight loss, the need for a long-term strategy, and treatment options
• Agree

  • Agree on realistic weight-loss expectations, targets, behavioral changes, and specific details of the treatment plan
• Arrange/assist

  • Assist in identifying and addressing barriers
  • Provide resources
  • Assist in finding and consulting with appropriate providers
  • Arrange regular follow-up.

Figure 3.

Greater weight loss associated with better adherence to components of comprehensive lifestyle management. Results from the Look AHEAD trial demonstrated that greater 1-year weight loss was associated with greater proportion of visits attended, more minutes per week of physical activity, and greater meal replacement use. Mean weight loss for each quartile is indicated outside of each bar. Mean adherence values (percent of visits, minutes of weekly activity, and number of mean replacements) for each quartile are indicated inside each bar. ILI, intensive lifestyle intervention; Look AHEAD, Action for Health in Diabetes. White bars represent first quartile; light gray bars represent second quartile; medium gray bars represent third quartile; and dark gray bars represent fourth quartile.

Summary

Management of obesity as a chronic disease begins by identifying individuals who may benefit from treatment. BMI is an acceptable measure for screening to identify individuals who may be at increased risk for cardiometabolic and other obesity-related complications. For individuals with elevated BMI, the decision to initiate obesity management should be confirmed by the risk or presence of obesity-related complications. Additional consideration of the severity of complications can guide the choice of an individualized therapeutic course, including determination of the benefits and risks of interventions in the context of potential adverse consequences of the disease.

Current treatment recommendations provide guidance regarding the appropriate intervention for obesity management based on the assessment of disease severity and potential treatment risks and benefits. Intensive lifestyle intervention is considered appropriate for all individuals with obesity, but because bariatric surgery and pharmacotherapy are associated with greater risk of adverse outcomes, they are generally reserved for patients with more severe disease. Pharmacotherapy is recommended as an appropriate option for individuals with BMI ≥ 27 kg/m² and complications or with BMI ≥ 30 kg/m² , consistent with label indications for approved agents; bariatric surgery is an option for individuals with BMI ≥ 35 kg/m² and complications or with BMI ≥ 40 kg/m² . In addition to considering the inherent risks and benefits of the therapeutic intervention, clinicians and patients should determine what level of risk the patient is willing to accept when developing an obesity treatment regimen.

Ultimately, weight loss targets and approaches should be determined collaboratively by the patient and clinician and should be based on an overarching goal of improved health. The recommended minimum initial goal for weight loss to improve health is 5%-10%, although greater weight loss yields greater benefits and may be necessary to ameliorate certain weight-related complications. More ambitious goals require greater commitment and effort. Accordingly, clinicians should educate patients regarding the efforts required to meet their weight loss goals and should work with patients to identify regimens that provide an acceptable balance of therapeutic benefit and risk of adverse outcomes and that will facilitate patient adherence.

Expert Perspectives on Supporting Lifestyle Management: Constructing a Toolbox of Successful Approaches

Comprehensive lifestyle management: Strategies associated with success

Comprehensive lifestyle management is regarded as the core approach to weight loss and obesity management and is considered appropriate for all individuals who are candidates for treatment (Figure 2) (4–6,20,21). The three principal components of comprehensive lifestyle management are reduced calorie intake, increased physical activity, and behavioral intervention (Table 3) (5,6,60). Behavioral intervention is an essential aspect because it imparts patients with strategies, such as modifying cues that lead to unwanted behaviors and self-monitoring, that promote treatment adherence and achievement of dietary and physical activity goals (60). Not surprisingly, better adherence to these components is associated with greater weight loss (Figure 3) (59).

As outlined in the ACC/AHA/TOS guidelines, anticipated mean weight loss associated with comprehensive lifestyle intervention is approximately 8%, which is in the range of 5%-10%, over 6–12 months (5). In fact, large key studies, particularly the Diabetes Prevention Program (DPP), the Action for Health in Diabetes (Look AHEAD) trial, and the National Weight Control Registry (NWCR), have shown that substantial proportions of individuals can achieve and maintain clinically meaningful weight loss of 5%-10% through lifestyle management (61–64). However, it should be noted that even with the best of behavioral interventions, some patients are not successful in achieving even modest weight loss.

The DPP and Look AHEAD trials evaluated the impact of intensive lifestyle management regimens that included projected weight loss goals of 7% of initial body weight, increased physical activity (≥150 min/week in DPP and ≥175 min/week in Look AHEAD), frequent interaction with trained interventionists (two to four sessions/month in the first 6 months), and long-term follow-up (61,62). In the DPP study, 50% of participants achieved 7% weight loss in 24 weeks (61); greater dietary self-monitoring, reflected in the number of fat intake records, was positively related to meeting both the physical activity and study weight loss goals (65). In the first year of the Look AHEAD study, 68% of participants experienced ≥5% weight loss, 55% reached >7% weight loss, and 38% of participants lost ≥10% of their initial body weight (66,67). Among Look AHEAD study participants who lost ≥10% in the first year of the study, 42% and 39% maintained the loss at 4 and 8 years, respectively (67,68). Session attendance and use of meal replacements were strategies associated with greater weight loss in the first year of the Look AHEAD trial, as was adherence to physical activity (Figure 3) (59). Similarly, at year 8 of the Look AHEAD trial, use of meal replacements, weight monitoring, and increased exercise were associated with weight loss maintenance (67).

The NWCR is the largest, prospective investigation of successful, long-term weight loss maintenance (63,64). NWCR entry requires ≥13.6 kg (29.2 lb) initial weight loss and maintained weight loss of at least 13.6 kg (29.2 lb) for ≥1 year (63,64). On average, registry members have lost 29.9 kg (66 lb) and kept it off for 5.5 years, although individual weight losses range from 13.6 to 136 kg (30–300 lb), and individual duration of successful weight loss has ranged from 1 to 66 years (64). General findings from the NWCR have identified several strategies used by participants to maintain weight loss: 78% eat breakfast every day, 75% weigh themselves at least once each week, 62% watch <10 h of TV per week, and 90% exercise about 1 h per day (64). Among the subset of NWCR participants who maintained weight loss for 10 years, behavior changes that could be associated with decreased self-monitoring were associated with weight regain, such as lower leisure-time calorie expenditure, restraint, self-weighing frequency, and higher fat intake and disinhibition (69). Some NWCR participants reported using prescription weight loss medications to lose weight or maintain weight loss, although the percentage is low (≤2.1%) (70).

Results from the DPP and Look AHEAD trials, and the NWCR, demonstrate that self-monitoring is a critical component of behavioral modification for weight loss. For example, monitoring of food intake, physical activity, and weight were essential components of DPP and Look AHEAD trial, and observations from the NWCR indicate that frequent weighing is associated with long-term success. Use of meal replacements, which reinforce self-monitoring to facilitate dietary restriction, is another common strategy that can be used to successfully lose and maintain weight (59,65,67,68). Additionally, frequent contact with a trained interventionist should be considered to support skill-building to achieve and sustain behavioral changes, as this approach was associated with greater weight loss over time (59,61,62,68).

Implementing successful behavioral strategies: Tools and approaches to support self-monitoring

Consistent with observations from the DPP, Look AHEAD, and NWCR, current recommendations for the management of obesity in adults highlight the importance of self-monitoring and frequent, continued feedback from trained interventionists to promote long-term weight loss (Table 3) (5,6). Accordingly, the ACC/AHA/TOS treatment guidelines include regular self-monitoring of food intake, physical activity, and weight as part of a structured behavior change program to support adherence to diet and physical activity goals (5); the ASBP algorithm includes a number of specific suggestions for self-monitoring of physical activity: daily activity logs, pedometer/ accelerometer logs, dynamic training metrics (miles run, laps swum, etc.), resistance training metrics (muscle circumference measurements, reps, sets, etc.), and percent body fat measurements (6).

Technological advances have led to the development of new tools and approaches that may help individuals who are trying to lose weight with self-monitoring of daily food intake and progress toward physical activity goals. Some examples include (25–29,71–74):

• Personal activity monitors: pedometers, sports watches, and activity trackers (e.g., BodyMedia FIT, DirectLife, FitBit, ActiGraph, Jawbone UP, and Basis BI)

• Websites: ChooseMyPlate and SparkPeople

• Phone applications: CalorieKing, GoMeals, Fitter Fitness Calculator, Charity Miles, SparkPeople, Strava Cycling, South Beach Diet, and MyFitnessPal

• Online social networks: Fitscape/iWell

This list identifies only a few options, whereas many more are available to suit individual needs and preferences. In fact, personal electronic devices (e.g., mobile phones and tablets) are becoming increasingly common in healthcare settings; health and fitness was reportedly the fastest growing app category in 2014, and MyFitness-Pal was the most downloaded health and fitness app (74). These tools have the potential to be convenient, cost-effective, and wide-reaching, but attrition rates can be high, and further assessment is needed to elucidate their role for individualized obesity management (71–73).

Initial studies have provided insight into some of the characteristics of newer technological approaches that may support weight loss strategies, particularly self-monitoring. For example, a retrospective cohort study of SparkPeople—a free online weight loss program— was conducted to identify website usage characteristics, such as numbers of log-in days, food entry days, exercise minutes, forum posts, weight entry days, exercise entry days, SparkPoints, and friends, that were associated with greater weight loss (73). A cohort of members who joined the program from February 2008 to April 2008 was identified, and follow-up data were collected through May 2010. Of the 521,000 people who joined SparkPeople in the specified timeframe, an initial cohort of 26,582 individuals with a baseline weight was identified through systematic random sampling (73). The final study cohort included those individuals from the initial cohort who had more than one weight entry (n = 5,595) and who used website features between their first and last weight entries (n = 1,258, mean BMI = 31.6 kg/m², mean age = 33.6 years) (73). Website usage variables associated with greater weight loss included number of weight entry days and number of forum posts (73); mean weight loss was significantly greater, by 5.1 kg, for individuals who had four or more weight entry days per 30 days vs. those with less than four, and members with at least one forum post experienced significantly greater weight loss, by 1.55 kg, vs. those with no forum posts (73). Consistent with observations from DPP, Look AHEAD, and NWCR data, regular weight monitoring, reflected in greater weight entry days, was associated with greater weight loss.

The potential impact of online social networking (OSN) on weight management has generated interest, because it has the potential to create a social support community in a convenient and accessible way. However, this approach is still in early stages of evaluation. In a 6-month, randomized, controlled trial including employees of a nonprofit healthcare organization and their family members (n = 349), participants were assigned to a control group or to the OSN arm (29). Both groups received printed materials on diet and exercise guidelines, meal plans, and the benefit of exercise and healthy eating (29). The OSN group was also given access to iWell—a platform for online networking and data downloading— and digital accelerometers and scales to monitor and download physical activity and weight information (29). Using the iWell network, participants could connect with identified contacts, make public postings, view their contacts’ postings, send individual messages, set goals, receive motivational messages, and compete in physical activity against other network members (29). Relative to control group participants, OSN group participants significantly increased their weekly leisure walking (164% vs. 47% increase, respectively) and experienced significantly greater weight loss (5.1 lb vs. 1.6 lb, respectively) (29). Walking and weight changes were related to the number of messages sent; more messages were associated with greater improvements in these measures (29). OSN has the capacity to combine self-monitoring (an effective strategy based on DPP, Look AHEAD, and NWCR observations) with group interaction, which has also been associated with better long-term weight loss maintenance, presumably due to greater empathy, social support, and competition (24,60). Research in this arena is only beginning to emerge and deserves careful observation.

Implementing successful behavioral strategies: Selecting dietary and exercise regimens that encourage adherence and facilitate self-monitoring

Consideration of patient preferences and individual needs is an important, overarching strategy in the collaborative management of obesity as a chronic disease. A patient may gravitate to a specific strategy because it is easier to use or fits into their lifestyle. Therefore, it is reasonable to expect that tools and approaches that suitably address the patient’s individual preferences, therapeutic needs, and weight loss barriers will likely be more effective and encourage treatment adherence. Furthermore, it may be possible to select multiple tools, approaches, and regimens that are mutually complementary.

Current evidence indicates that a variety of dietary approaches are effective at producing weight loss in adults with overweight or obesity (5). For instance, recent evidence-based guidelines from ACC/ AHA/TOS specifically recommend prescribing a diet that is consistent with the patient’s preferences and health status, noting that referral to a nutrition professional for counseling is preferred (5). Generally, calorie intake can be restricted by setting a daily limit on the number of calories (≈800–1,500 kcal/day for a low-calorie diet), reducing the number of calories each day by ≈500–750 kcal, and/or limiting consumption of a specific type of food, such as fats or carbohydrates (5,6). Examples of several popular reduced-calorie diets are listed in Table 5 (75).

TABLE 5.

Examples^a of reduced-calorie diets for weight loss

Diet	Description
Weight Watchers	Point system based on food characteristics encourages healthy choices
	Group support available
Health Management Resources Diet	Meal replacements, fruits, vegetables Quick start and transition phases
	Lifestyle training, weekly coaching, home or clinic
Biggest Loser Die	Books providing guidance on calorie restriction and exercise
Jenny Craig	Personalized prepackaged meal/exercise plan with support of consultants with access to expertise of registered dietitians
Raw Food Diet	75%-80% of daily foods are plant based and not heated above 1158F or 46.18C
	Substantial preparation time
Volumetrics	Focus on low-density, high-volume foods
Atkins	Low carbohydrate
	Frozen food line is available
Flexitarian Diet	Mostly vegetarian
	Outlined 5-week meal plan
Slim-Fast	Meal replacement program
Vegan Diet	Excludes all animal products

^aMany reduced-calorie diet options are appropriate for individuals who would benefit from weight loss, and selection should take into account patient preferences and health status; additional information on these and other weight loss diets is provided in U.S. News and World Report.

Recent guidelines also include meal replacements as an option for weight management, citing supporting evidence pertaining to their use over a 6-month time frame, but acknowledging that the strength of evidence is low (5). As illustrated in Figure 3, the use of meal replacements was associated with greater weight loss over 1 year in the Look AHEAD trial (59), and several studies reviewed by Wadden et al. (24) have demonstrated greater weight loss with incorporation of meal replacements, compared with reduced-calorie diets of conventional foods. Furthermore, significantly greater weight loss was associated with portion-controlled servings of conventional foods or provision of detailed menus. Some examples of programs that incorporate prepackaged meals or meal replacements are included in Table 5 (75).

Additionally, recent evidence from NWCR suggests that use of low- or no-calorie sweetened beverages may be another helpful dietary strategy (76). Among the 434 surveyed NWCR participants, 53% indicated that they regularly consumed low- or no-calorie sweetened beverages, and ≥40% indicated that changing beverage consumption patterns was very important to losing weight and maintaining weight loss (76). Therefore, in addition to selecting dietary options that match patients’ preferences and needs, it may also be possible to select options that facilitate self-monitoring, such as portion-controlled diets, or dietary mechanisms that obviate the need for self-monitoring, such as consumption of low- or no-calorie sweetened beverages.

Furthermore, current treatment recommendations address the need to individualize the physical activity component of comprehensive lifestyle management (5,6). Assuming the individual is ready and willing to increase their physical activity, prior to starting an exercise program, a medical evaluation should be performed to assess their current activity level; mobility, fitness, and equipment needs; the need for additional testing (e.g., cardiac stress testing); and any potential medication adjustments (6). An exercise prescription should be provided and should include the agreed upon type or types of activity, frequency, level of intensity, time commitment, enjoyment level, and a back-up plan (6). Indication of a specific metric (e.g., number of steps walked and number of exercise minutes) may also be helpful in supporting the individual with self-monitoring their activity level (6). It is important to remember that exercise options may be restricted for some individuals based on their degree of mobility; a patient will not be able to monitor and perform a record of physical activity if they cannot participate in it (6). For example, for an individual who is unable to walk, choices may be limited to activities such as seated or aquatic exercises, whereas a patient with no substantial mobility limitations may select from a broader range of activities, as guided by the clinician (6). In addition to dynamic and resistance training, patients should also consider increasing energy expenditure through leisure-time activity (e.g., dancing), transportation (e.g., walking short distances), and occupational means (e.g., taking the stairs rather than the elevator) (6). So, similar to dietary recommendations, options for increasing physical activity should match patients’ needs and preferences, yet still support self-monitoring.

Implementing successful behavioral strategies: Tools and approaches to support frequent interventionist contact and personalized feedback

Frequent, personalized feedback from trained interventionists is emphasized by the ACC/AHA/TOS guidelines and the ASBP algorithm as an important strategy for supporting behavioral change in comprehensive lifestyle management (5,6). Recommendations by both groups indicate that interventionists need not be physicians; other healthcare professionals who are trained in formal obesity management protocols, including dietitians, psychologists, exercise specialists, health counselors, etc., may provide personalized feedback (5,6). Notably, the ACC/AHA/TOS guidelines provide specific guidance regarding the nature and frequency of interactions with trained interventionists. For initial weight loss, individuals should ideally participate in a comprehensive lifestyle management program that includes onsite, high-intensity interventions (i.e., ≥14 sessions in 6 months) provided by a trained interventionist (5). Participants who successfully lose weight should be advised to participate in a long-term (≥1 year) weight loss maintenance program that includes monthly, or more frequent, in-person or telephone contact with a trained interventionist (5).

Alternatively, delivery of weight loss intervention via telephone or other electronic medium may be appealing to some patients and healthcare professionals because of potential barriers associated with face-to-face delivery, such as time commitment, expense, loss of anonymity, time away from work, etc. (77). However, it should be noted that the ACC/AHA/TOS guidelines caution that these methods may be less effective for encouraging weight loss than face-to-face interventions (5). This was demonstrated in a 6-month comprehensive weight loss trial (n = 481) comparing the impact of weekly meetings held in person, as face-to-face group meetings; via the internet, as a chat group; or in a hybrid format, with all sessions held as an internet chat group except one face-to-face meeting per month (78). At 6 months, mean weight loss was found to be significantly greater for the in-person format compared with the hybrid and internet formats (7.6, 5.7, and 5.5 kg, respectively; P < 0.01 for in-person vs. the other interventions) (78). Not surprisingly, the out-of-pocket cost per person was higher for the in-person format ($706/ person) compared with the internet format ($372/person) (79). Furthermore, a 24-month, randomized, controlled trial (n = 415) compared three program delivery methods: self-directed; electronically delivered (by phone, website, and e-mail); and in-person (electronically delivered with added group and individual sessions) (80). In this trial, mean weight loss for electronic and in-person programs was similar (4.6 and 5.1 kg, respectively), as were the proportions of individuals with ≥5% weight loss (38.2% and 41.4%, respectively) (80). For these reasons, clinicians and weight loss program participants should consider and evaluate effectiveness, time commitment, convenience, and cost in determining the best, individualized option for delivery of weight loss program support.

Summary

Comprehensive lifestyle management is the core intervention for the treatment of adult obesity. When implemented successfully, it can lead to long-term, clinically meaningful weight loss in a substantial number of individuals. Comprehensive lifestyle management includes three key components: reduced calorie intake, increased physical activity, and behavioral intervention. Behavioral intervention supports the other two components by helping individuals who are trying to lose weight identify strategies that promote adherence to diet and exercise regimens. Self-monitoring and frequent contact with trained interventionists are two strategies that are commonly associated with weight loss success. Technological advances, including electronic resources to receive feedback from interventionists and to monitor diet and exercise, provide individuals trying to lose weight with newer options for implementing these strategies. However, these strategies and tools are likely to be less effective if dietary and physical activity regimens are not individualized to meet patients’ needs and preferences. Current treatment recommendations outline the elements of comprehensive lifestyle management regimens and provide suggestions for individualization, but ultimately, the patient and clinician will need to discuss and agree to an overall approach that includes dietary and physical activity goals as well as strategies to achieve those goals and tools or approaches to implement the strategies.

Expert Perspectives on Pharmacotherapy for Obesity Management: Focus on New Therapeutic Approaches to Meet Individual Needs

Dysregulation and adaptive responses of energy balance physiology as mechanisms of weight gain and loss: Rationale for the use of adjunct pharmacotherapy in the management of adult obesity

Despite their best attempts, many individuals cannot successfully achieve long-term weight loss, even with extremely effective lifestyle intervention programs such as those used in the DPP and Look AHEAD trials (61,67,68,81). Additionally, research over the last 10–15 years has focused on and led to increased understanding of systems that regulate appetite and food intake. These investigations have revealed that patients who need to lose weight are likely fighting against dysregulated physiologic mechanisms that oppose weight loss and contribute to the maintenance of higher body weight (21,82–84).

In normal physiology, homeostatic signals from peripheral organs and the central nervous system (CNS) coordinately regulate energy intake, energy expenditure, and maintenance of body weight (82–84). The stomach, adipose tissue, intestines, and pancreas produce hormones that reflect fuel availability and the need for additional fuel (Figure 4) (21,82–84). For example, as energy stores decrease, fat cells get smaller, leptin levels go down, and food intake increases. As energy stores increase, fat cells get larger, leptin levels go up, and food intake is decreased. Most of the peripheral hormones regulate appetite signals for decreased food intake (anorexigenic response); only ghrelin stimulates increased food intake (orexigenic response). The peripheral appetite-regulating hormones act on orexigenic and anorexigenic neurons in the arcuate nucleus of the hypothalamus within the CNS, which in turn relay signals to the paraventricular nucleus and higher cortical centers. Arcuate nucleus neurons that secrete neuropeptide Y and agouti-related protein stimulate orexigenic responses, and those that express proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript signal for anoindividual loses weight,rexigenic responses (82–84). However, other CNS pathways have been shown to influence food intake (84). Executive functions can drive appetite from the higher cortex, input from the olfactory bulb and mesolimbic system mediate hedonistic eating behaviors, and signals from the brainstem and the autonomic nervous system also contribute. Multiple neurotransmitters and circuits are involved, including gamma-aminobutyric acid, dopamine circuits that mediate reward and pleasure, and serotonin pathways that impact memory, depression, and food (84).

Figure 4.

Regulation of energy intake. Peripheral signals originate from the stomach, adipose tissue, intestines, and pancreas, which produce hormones that act on neurons in the arcuate nucleus of the hypo-thalamus. In general, action on NPY/AgRP neurons stimulates food intake via the orexigenic pathway (indicated by gray lettering and arrows and white shapes with gray outlines), and action on POMC/CART suppresses food intake via the anorexigenic pathway (indicated by black lettering and arrows and line-filled shapes). Of the peripheral hormones, ghrelin is orexigenic; leptin, CCK, GLP-1, peptide YY, amylin, and insulin are anorexigenic. 5-HT_2c, serotonin 2c receptor; aMSH, alpha-melanocyte-stimulating hormone; µ-OR, mu-opioid receptor; AgRP, agouti-related protein; BDNF, brain-derived neurotrophic factor; CART, cocaine- and amphetamine-regulated transcript; CCK, cholecystokinin; DA, dopamine; DMN, dor-somedial nucleus; GABA, gamma-aminobutyric acid; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; GSHR, glutathione reductase; LepR, leptin receptor; LHA, lateral hypothalamic area; MC4R, melanocortin 4 receptor; MCH, melanin-concentrating hormone; MCH1R, melanin-concentrating hormone receptor 1; NE, norepinephrine; NPY, neuropeptide Y; NTRK2, neurotrophic tyro-sine kinase receptor type 2; POMC, proopiomelanocortin; PVN, paraventricular nucleus; Y1R, neuropeptide Y receptor Y1; Y2R, neuropeptide Y receptor Y2; Y5R, neuropeptide Y receptor Y5.

In individuals with obesity, pathways that impact food intake are dysregulated to favor energy intake and metabolic conservation over energy expenditure, consequently resulting in a higher body weight (84). In this circumstance, homeostatic mechanisms work to maintain the new, higher body weight by countering weight loss (84). As an individual loses weight, ghrelin levels increase and levels of anorexigenic hormones (leptin, peptide YY, cholecystokinin, and amylin) decrease, leading to increased food intake. Additionally, resting energy expenditure decreases; so, less energy is spent, and hunger increases, leading to preferences for calorie-dense foods. Thus, physiological alterations associated with obesity converge with mechanisms that promote energetic homeostasis to maintain high body weight, promote energy intake and weight gain, and increase the difficulty of achieving weight loss (84). Supporting evidence indicates that the physiological alterations that counter weight loss are sustained >1 year, supporting acknowledgement of obesity as a chronic disease and emphasizing the need for long-term disease management (1–6,21).

By attenuating the mechanisms that promote or contribute to weight gain and maintenance, weight loss medications may help individuals manage physiological barriers that can impede other approaches to weight loss. Furthermore, when used in combination with comprehensive lifestyle management, weight loss medications have been shown to increase the probability that individuals will achieve and sustain clinically meaningful weight loss (21,85). This can, in turn, yield multiple health benefits for the patient, consistent with the over-arching goals of obesity management (21,85).

Addressing the use of pharmacological agents in managing adult obesity: Current treatment recommendations

In the United States, a number of pharmacological agents are approved for weight loss in adults as adjunct therapies to be used in combination with a reduced-calorie diet and increased physical activity (30). At the present time, four agents (phentermine, diethyl-propion, phendimetrazine, and benzphetamine) are approved for short-term weight management (≤12 weeks) and five agents are approved for long-term weight management (orlistat; a combination of phentermine and extended-release [ER] topiramate; lorcaserin; a combination of naltrexone ER and bupropion ER; and liraglutide 3.0 mg/day) (30,85). Of the agents approved for long-term use, all but orlistat have been approved since 2012, leading to a rapid increase in the number of available weight loss agents from 2012 to 2015 (30). Recent treatment recommendations provide guidance, in conjunction with product-specific prescribing information, regarding the safe and effective use of adjunct pharmacotherapy for weight loss, including newer agents (6,21,30). Specifically, an evidence-based clinical practice guideline on the pharmacological management of obesity was recently published by the ES and cosponsored by TOS and the ESE (21).

The recent ES/TOS/ESE guidelines recommend the use of weight loss pharmacotherapy based on a high-quality evidence rating and are consistent with other recommendations and prescribing information for weight loss agents (4–6,21,30). The following are strong recommendations based on high-quality evidence (4–6,21):

• Pharmacotherapy is recommended as an adjunct to comprehensive lifestyle management for individuals with BMI > 30 kg/m² or with BMI ≥ 27 kg/m² with comorbidity (e.g., hypertension, dyslipidemia, type 2 diabetes, and obstructive sleep apnea) and who meet label indications.

• Individuals who have been unable to successfully lose and maintain weight are candidates for weight loss pharmacotherapy.

However, the ES/TOS/ESE guidelines also provide more specific guidance regarding the use of weight loss pharmacotherapy; these recommendations are summarized below, accompanied by the quality of supporting evidence (21).

• Suggest that practitioners use approved weight loss medication, over no pharmacological therapy, to promote weight maintenance in order to ameliorate comorbidities and increase adherence to behavior. (Weak recommendation, low-quality evidence)

• Suggest that providers assess the safety and efficacy of prescribed weight loss medication at least monthly for the first 3 months and at least every 3 months thereafter. (Weak recommendation, low-quality evidence)

• Recommend continuation of prescribed weight loss medication if it is safe and the patient loses ≥5% of body weight at 3 months; discontinue prescribed weight loss medication and consider alternative medication or referral for alternative treatment approaches if there are safety or tolerability issues at any time or if the patient loses <5% of body weight at 3 months. (Strong recommendation, high-quality evidence)

• Suggest that providers initiate pharmacotherapy with dose escalation, based on efficacy and tolerability, to the recommended dose and not exceeding the highest recommended dose. (Weak recommendation, low-quality evidence)

• For patients with type 2 diabetes and overweight or obesity, suggest the use of antidiabetic agents that promote weight loss (e.g., GLP-1 receptor agonists and sodium glucose cotransporter-2 inhibitors) in combination with first-line metformin. (Weak recommendation, moderate-quality evidence)

• Recommend that providers avoid use of phentermine and diethyl-propion for individuals with uncontrolled hypertension or a history of heart disease. (Strong recommendation, moderate-quality evidence)

• Suggest that providers use agents that are not sympathomimetics for individuals with CVD who seek pharmacotherapy for weight loss (e.g., consider agents such as lorcaserin or orlistat) (Weak recommendation, very low-quality evidence)

The potential role of weight loss agents that are approved for short-term use in the chronic management of obesity is also addressed by the ES/TOS/ESE guidelines (21). Specifically, these guidelines include a section on long-term use of phentermine, the most widely prescribed of the weight loss agents approved for short-term use (21,85). Notably, phentermine is not approved for long-term use; so, prescribing this agent long term represents an off-label use that is subject to regulations of State Medical Boards that carry the enforcement of federal and local laws, which take precedence if they are provided (21). Although the addiction potential of phentermine with long-term use (>1 year) may be low (86), there is still abuse potential with this agent that must be considered. In a 28-week trial comparing phentermine with a combination of phentermine and topiramate ER, significantly greater weight loss was demonstrated with a combination of 7.5 mg phentermine and 46 mg topiramate ER vs. 15 mg phentermine alone (8.5% vs. 6.1%, P<0.05) (87). Aside from these two studies, long-term data on the efficacy and safety of phentermine are not available (21). Importantly, if phentermine is considered as an option for long-term use, it is crucial to ascertain and document in the patient’s medical record that the patient:

• Has no evidence of serious CVD

• Does not have a serious psychiatric disease or a history of substance abuse

• Has been informed about weight loss medications that are approved by the US Food and Drug Administration (FDA) for long-term use and has been told that the medications approved for long-term use have documented safety and efficacy

• Does not experience a clinically significant increase in pulse or blood pressure with phentermine

• Demonstrates significant weight loss while using phentermine.

Furthermore, dosing should only be increased if the patient is not achieving clinically significant weight loss. Again, the fact that phentermine is being used off label should be documented each visit, and the patient should be followed monthly during dose escalation and at least every 3 months once a stable dose is reached (21). This discussion notwithstanding, the authors recommend against the use of phentermine on a long-term basis, and strongly recommend agents that have been approved for long-term use, which have been evaluated for safety and efficacy in US FDA-sanctioned clinical trials.

Importantly, the ES/TOS/ESE guidelines offer specific recommendations regarding the role of pharmacotherapy to promote long-term weight maintenance and criteria for continued use of weight loss medications (21). These recommendations are especially noteworthy because they are more consistent with recognition of obesity as a chronic condition that requires persistent and sustained management efforts (1–6). In fact, evidence supports the long-term use of pharmacotherapies for weight maintenance. Extended trials of agents recently approved for long-term use illustrate the importance of continuing treatment with weight loss pharmacotherapy to limit regain (88–90). In 2-year trials for orlistat (89) and lorcaserin (88), patients in one treatment arm switched from active treatment to placebo at 1 year (Figure 5). In both studies, weight increase was greater in the group that switched to placebo than in the group that was maintained on the weight loss agent. Using a different study design, the liraglutide SCALE-Maintenance trial demonstrated the ability of liraglutide 3.0 mg to limit weight regain and to promote further weight loss, in participants who successfully lost >5% body weight in a lifestyle management run-in period (Figure 6) (90). Significantly more participants maintained a weight loss ≥5% with liraglutide 3.0 mg (81%) vs. placebo (49%), and significantly more lost additional weight after the run-in with liraglutide 3.0 mg vs. placebo— 51% vs. 22% lost ≥5% and 25% vs. 6% lost≥ 10% (P < 0.001 for all liraglutide 3.0 mg comparisons with placebo) (90). In addition, two studies using a similar study design demonstrated that, for individuals who achieved significant weight loss through low-calorie diets with no adjunct therapy, those who added orlistat (120 mg, three times daily) following weight loss regained significantly less weight over 1 year (91) or 3 years (92) vs. those who received placebo.

Figure 5.

Preventing weight regain with long-term pharmacotherapy (2-year cross-over data). Changes in body weight in 1-year extension following a 1-year trial demonstrate better weight loss maintenance with pharmacological intervention versus placebo. In addition, participants in the intervention group were reassigned at 1 year to continue weight-loss medication or placebo. Results indicate greater weight regain for groups switched from medication to placebo. BW, body weight; DB, double-blind; SB, single-blind lead-in period. ^aParticipants were reassigned to continue or switch treatment at 1 year; ITT population (n=683 for year 1 and n=519 for year 2; 83% female); mean baseline characteristics: BMI=36 kg/m², and age=44–45 years; ^bParticipants in the lorcaserin group in year 1 were re-randomized to continue lorcaserin or switch to placebo at the beginning of year 2 whereas those in the placebo group in year 1 continued on placebo (n=1,553; 83%-84% female at year 1 baseline); mean baseline characteristics: BMI=36 kg/m² and age=44 years.

Figure 6.

Maximizing weight loss by phased therapy of intensive lifestyle intervention and medication: weight-loss maintenance and additional weight loss with liraglutide 3.0 mg following initial weight loss with highly-structured diet. After an initial period of highly structured, low-energy (1,200–1,400 kcal/day) diet for 4–12 weeks, all participants who achieved ≥5% weight loss were randomized to liraglutide (3.0 mg daily) or placebo and continued behavioral intervention. Participants in the liraglutide 3.0 mg group lost additional weight, and participants in the placebo group regained slightly over 1 year. Participants (n= 422) had mean run-in weight (week 12) of 105.9 kg and mean randomization weight (week 0) of 99.6 kg. F, follow-up; LIRA, liraglutide; PBO, placebo; S, screening. ^aP<0.0001 vs. PBO.

Addressing patient needs and preferences: Considering the characteristics of pharmacotherapies approved for long-term weight management

Current treatment recommendations indicate that using medications approved for weight loss adjunct to lifestyle management may be an appropriate approach to obesity management for some individuals (4–6,21). Moreover, agents assessed and approved for long-term weight management may be more suitable, because obesity is recognized as a chronic disease that requires persistent, ongoing intervention efforts (4–6,21). In the United States, several agents have only recently been approved for the indication of long-term weight management, and the characteristics of agents for long-term weight management vary considerably. Therefore, an overview of these medications is provided to improve understanding among clinicians regarding their use for the management of overweight and obesity. Information on 1-year efficacy, common adverse reactions, contraindications, and warnings and precautions is summarized in Tables 6–9, respectively (30). Additional information regarding these topics is provided later. However, because the corresponding prescribing information for each medication is the most authoritative document regarding its clinical characteristics and use, including details on dosage and administration, clinicians who intend to prescribe these medications for their patients should refer to this important clinical resource (30).

TABLE 6.

One-year efficacy for recommended doses of medications approved for long-term weight management in the United States^a

Agent	Dosage	Efficacy, difference vs. PBOb
		Mean weight change (%)	Patients losing ≥ 5% of initial weight (%)	Patients losing ≥ 10% of initial weight (%)
Orlistatc	120 mg thrice daily	−3.0	≈21	≈12
Lorcaserind	10 mg twice daily	−3.3	25	14
Phentermine/topiramate ERe,f	7.5 mg/46 mg once daily	−6.6	41	30
Naltrexone ER/bupropion ERe,g	8 mg/90 mg 2 tablets twice daily	−4.1	25	14
Liraglutidee,h	3.0 mg once daily	−4.5	28	19

ER, extended release; PBO, placebo.

^aData are not from head-to-head trials of weight loss agents, but they suggest that the range of average weight loss will be approximately 3%-6% above PBO at 1 year at recommended doses.

^bData are presented as PBO-subtracted differences, with all differences significant versus PBO (P< 0.05)

^cData from five clinical trials for orlistat; pooled data for mean weight loss and estimated difference between averages across five trials for each treatment group for categorical weight loss; proportion achieving ≥5% or ≥10% weight loss was significantly greater for orlistat vs. PBO group in each trial.

^dCombined data from two clinical trials (study 1 and study 2) for lorcaserin, conducted in patients without diabetes.

^eFour-week titration followed by 52-week treatment period.

^fData from study 2 in overweight or obese patients with comorbidities; results using 15 mg/92 mg dose are not included, because this dose is recommended only for individuals who do not achieve >3% weight loss over 12 weeks at 7.5 mg/46 mg dose.

^gData from COR-1 trial in patients with overweight or obesity and at least one of hypertension or dyslipidemia.

^hData from study 1 in patients with overweight and obesity with at least one weight-related comorbidity, although patients with diabetes were excluded.

TABLE 9.

Warnings and precautions for medications approved for long-term weight management in the United States

Agent	Warnings and precautions
Orlistat	Decreased cyclosporine exposure
	Supplement requirement (fat-soluble vitamins) Increased urinary oxalate -monitor if risk of renal impairment
	Increased gastrointestinal effects with high-fat diet Liver injury (rare)
	Substantial weight loss can increase risk of cholelithiasis
Lorcaserin	Serotonin syndrome or NMS-like reaction
	Valvular heart disease
	Cognitive impairment
	Psychiatric disorders
	Depression/suicidal thoughts
	Hypoglycemia (when used with antidiabetic medications)
	Priapism
Phentermine/topiramate ER	Fetal toxicity (REMS)
	Increased heart rate
	Suicidal behavior/ideation
	Acute myopia and secondary angle closure glaucoma
	Mood and sleep disorders
	Cognitive impairment
	Metabolic acidosis
	Elevated creatinine
	Hypoglycemia (when used with antidiabetic medications)
Naltrexone ER/bupropion ER	(Boxed warnings) Suicidal thoughts and behaviors, neuropsychiatric reactions
	Seizure risk -adhere to dosing schedule and avoid administration with high-fat meal to limit risk
	Increased blood pressure and heart rate -monitor
	Hepatotoxicity (naltrexone)
	Angle-closure glaucoma (antidepressant)
	Hypoglycemia (when used with antidiabetic medications)
Liraglutide 3.0 mg	(Boxed warning) Risk of thyroid C-cell tumors
	Acute pancreatitis
	Acute gall bladder disease
	Increased heart rate -monitor
	Renal impairment
	Hypersensitivity
	Suicidal behavior and ideation
	Hypoglycemia (when used with antidiabetic medications)

ER, extended release; NMS, neuroleptic malignant syndrome; REMS, Risk Evaluation and Mitigation Strategy.

Orlistat

Orlistat, approved by the US FDA in 1999, is an exception among medications currently approved for weight management in that it does not directly target appetite mechanisms (21,30). Instead, it is a gastrointestinal lipase inhibitor that prevents fat absorption (21,30,85). At the prescription dose of 120 mg, administered three times daily within 1 h of a meal, it prevents absorption of ≈30% of triglycerides in the stool; systemic absorption of orlistat is minimal (21,30,85).

Data on 1-year weight change with the prescription dose of orlistat are presented in Table 6 (30). The over-the-counter dose (60 mg) is associated with modest weight loss of 2%-3% over 12 months (21,85). Data on efficacy over more than 1 year are also available for orlistat at the 120-mg dose. In a 4-year study, mean weight loss from baseline was significantly greater with orlistat (5.8 kg) vs. placebo (3.0 kg, P< 0.001) (93). The trend for categorical weight loss was similar. The respective proportions of participants achieving ≥5% loss in the orlistat and placebo groups were 52.8% and 37.3% (P < 0.001); for weight loss ≥10%, the respective values were 26.2% and 15.6% (P > 0.001) (93).

Summaries of common adverse reactions, contraindications, and warnings and precautions included in the prescribing information for the 120-mg dose of orlistat are presented in Tables 7–9 (30). Gastrointestinal episodes were the most common adverse events associated with orlistat use in clinical trials; gastrointestinal adverse events were reported by ≥20% of clinical trial participants in the first year, although most episodes lasted <4 weeks (30). Among the patients treated with orlistat, 8.8% discontinued treatment due to adverse events vs. 5.0% of patients treated with placebo, and gastrointestinal adverse events were the most common reason for orlistat discontinuation (30). Limiting fat consumption to ≤30% of daily caloric intake may reduce the occurrence of gastrointestinal events (30). Coadministration of fiber-containing supplements may also decrease gastrointestinal adverse events (85). Because orlistat reduces the absorption of some fat-soluble vitamins, patients should also be advised to take a multivitamin supplement that includes fat-soluble vitamins at least 2 h before or after administration (e.g., at bedtime) (30).

TABLE 7.

Common adverse effects of medications approved for long-term weight management in the United States

Agent	Common adverse effectsa
Orlistat	Oily spotting, flatus with discharge, fecal urgency, fatty oily stool, increased defecation, fecal incontinence
Lorcaserin	In patients without diabetes: headache, fatigue, dizziness, nausea, dry mouth, constipation In patients with diabetes: hypoglycemia, headache, back ache, cough, fatigue
Phentermine/ topiramate ER	Paresthesia, dizziness, distorted taste, insomnia, constipation, dry mouth
Naltrexone ER/ bupropion ER	Nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, diarrhea
Liraglutide 3.0 mg	Nausea, hypoglycemia,b diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, increased lipase

ER, extended release.

^aAdverse effects occurring more commonly than with placebo in >5% of clinical trial participants.

^bSystematically captured only for patients with type 2 diabetes.

Lorcaserin

Lorcaserin suppresses appetite through activation of the serotonin 2C receptor (5-HT2c) on POMC neurons (Figure 4) (21,30,82–85). It is administered twice daily as a 10-mg tablet (30). As with other medications approved for long-term weight management, lorcaserin should be discontinued if it is ineffective (i.e., 5% weight loss is not achieved by week 12) (30). Data on 1-year weight change with lorcaserin are summarized in Table 6 (30). Two-year weight loss with lorcaserin, following a 1-year extension of a 1-year trial, is graphically depicted in Figure 5 (88). In the same trial, significantly more participants who achieved ≥5% weight loss at 1 year maintained ≥5% weight loss in the lorcaserin group vs. the placebo group (67.9% vs. 50.3%, P < 0.001) (88).

Summaries of common adverse reactions, contraindications, and warnings and precautions included in the prescribing information for lorcaserin are presented in Tables 7–9 (30). In clinical trials of ≥1 year duration, 8.6% and 6.7% of individuals in lorcaserin and placebo groups, respectively, discontinued treatment due to adverse events (30). Headache, depression, and dizziness were the adverse events that most commonly resulted in more discontinuations among lorcaserin vs. placebo-treated patients (30).

Lorcaserin is not recommended for individuals with severe renal impairment or end-stage renal disease and should be used with caution in individuals with moderate renal impairment or severe hepatic impairment (30). Prescribing information for lorcaserin also includes warnings and precautions on the possible risks of serotonin syndrome and neuroleptic malignant syndrome-like reactions (30). Serotonin syndrome is caused by an excess of serotonin, and it has been reported during use of serotonergic drugs, particularly when they are used in combination (30,94,95). Signs and symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular aberrations, and/or gastrointestinal symptoms (30). If signs or symptoms develop, lorcaserin should be discontinued, and the patient should receive supportive treatment (30,94,95). Furthermore, if use of lorcaserin in combination with other serotonergic agents is deemed clinically necessary, extreme caution and careful observation is advised (30).

Phentermine/topiramate ER

The phentermine component of phentermine/topiramate ER is a lower dose of the same noradrenergic agent that is indicated for short-term weight loss treatment; it acts on POMC neurons to suppress appetite (Figure 4) (21). Although it is not clear how topiramate suppresses appetite, its effect has been shown to be additive when used in combination with phentermine (21). Phentermine/topiramate ER is initiated through step-wise titration, starting at 3.75 mg/23 mg once daily for 14 days before increasing to the recommended dose of 7.5 mg/46 mg once daily (30). Further titration to a maximum dose of 15 mg/92 mg once daily may be considered for individuals who do not achieve 3% weight loss after 12 weeks (30). If 5% weight loss is not achieved after 12 weeks at 15 mg/92 mg per day, the phentermine/ topiramate ER dose should be gradually reduced for discontinuation (30). To prevent insomnia, evening dosing of phentermine/topiramate ER should be avoided (30).

Data on 1-year weight change with phentermine/topiramate ER are summarized in Table 6 (30). The effects of phentermine/topiramate ER over 2 years were demonstrated in a 1-year, double-blind extension of a 1-year randomized, controlled trial (96,97). Significant, sustained weight loss over 2 years was demonstrated with phentermine/topiramate ER 7.5 mg/46 mg vs. placebo (9.3% and 1.8% weight loss from baseline, respectively; P > 0.0001) (97). Proportions of individuals achieving ≥5% and ≥10% weight loss were also significantly greater for phentermine/topiramate ER 7.5 mg/46 mg vs. placebo; ≥5% weight loss was achieved by 75.2% and 30.0% of participants, respectively, and ≥10% weight loss was achieved by 50.3% and 11.5% of participants, respectively (P < 0.0001 for all comparisons vs. placebo) (97).

Summaries of common adverse reactions, contraindications, and warnings and precautions included in the prescribing information for phentermine/topiramate ER are presented in Tables 7–9 (30). In clinical trials, discontinuation rates due to adverse events were 11.6%-17.4% across phentermine/topiramate ER doses and 8.4% for placebo (30). Adverse reactions leading to discontinuation in ≥1% of participants treated with phentermine/topiramate ER were blurred vision, headache, irritability, dizziness, paraesthesia, insomnia, depression, and anxiety (30).

Although all weight loss agents are contraindicated in pregnancy, phentermine/topiramate ER has an accompanying Risk Evaluation and Mitigation Strategy because fetal exposure to topiramate in the first trimester of pregnancy has been associated with increased risk of oral clefts (30,85,98). For this reason, women of reproductive potential should be informed of the potential for fetal harm with phentermine/topiramate ER; a negative pregnancy test should be obtained before starting treatment and monthly thereafter; effective contraception should be used during treatment; and in the event of pregnancy, treatment should be discontinued (30). Healthcare providers and patients are encouraged to report pregnancies that occur during treatment with phentermine/topiramate ER to a pregnancy surveillance program established to monitor maternal-fetal outcomes (see phentermine/topiramate ER prescribing information) (30). Additionally, for individuals with moderate or severe renal impairment (CrCl < 50 ml/min) or in individuals with moderate hepatic impairment (Child-Pugh 7–9), the dose of phentermine/topiramate ER should not exceed 7.5 mg/46 mg per day (30). Use of phentermine/ topiramate ER should be avoided for individuals with end-stage renal disease on dialysis and for individuals with severe hepatic insufficiency (Child-Pugh 10–15) (30).

Naltrexone ER/bupropion ER

The mechanism by which the combination of bupropion and naltrexone promotes weight loss is not completely understood (30). Bupropion is a dopamine and norepinephrine reuptake inhibitor that stimulates POMC neurons, but its weight loss effects are modest, presumably due to inhibitory feedback, via beta-endorphin release, on the POMC neurons (Figure 4) (21,30,99). Naltrexone is an opioid receptor antagonist (30). It may potentiate the effect of bupropion by blocking beta-endorphin action at µ-opioid receptors, thereby limiting the inhibitory feedback on POMC neurons (Figure 6) (99). Titration of naltrexone ER/bupropion ER is described in detail in the prescribing information (30). After starting with one tablet (8 mg/90 mg) in the morning for the first week, one tablet is added each week, in morning or evening as indicated in the prescribing information, until a maintenance dosage of two tablets twice daily is reached (30). Naltrexone ER/bupropion ER should not be taken with a high-fat meal because of increased systemic exposure, and it should be discontinued if 5% weight loss is not achieved after 12 weeks at the maintenance dosage (30). Data on 1-year weight change with naltrexone ER/bupropion ER tablets are summarized in Table 6 (30).

Summaries of common adverse reactions, contraindications, and warnings and precautions included in the prescribing information for naltrexone/bupropion ER tablets are presented in Tables 7–9 (30). In clinical trials, discontinuation due to an adverse event was reported for 24% and 12% of individuals receiving naltrexone ER/bupropion ER or placebo, respectively (30). The adverse events that most often led to discontinuation of naltrexone ER/bupropion ER were nausea, headache, and vomiting (30).

Based on information for the constituent agents, the maximum recommended dose for individuals with moderate or severe renal impairment is 16 mg/180 mg, administered as an 8 mg/90 mg tablet morning and evening (30). For individuals with hepatic impairment, the maximum recommended dose for naltrexone ER/bupropion ER is 8 mg/90 mg per day, administered as one tablet in the morning (30). Because the antidepressant bupropion is an active component of this medication, the prescribing information includes a boxed warning regarding the potential for increased risk of suicidal thoughts and behaviors in children, adolescents and young adults (30). Notably, clinical trials did not identify associations between naltrexone ER/bupropion ER and suicidality, though potential relationships were investigated (100). Because naltrexone/bupropion ER use was associated with small but significant initial increases in blood pressure and heart rate in clinical trials, blood pressure and heart rate should be monitored during treatment, particularly among patients with cardiac or cerebrovascular disease. Naltrexone ER/ bupropion ER is contraindicated for individuals with uncontrolled hypertension (30). It is also contraindicated for use with other bupropion-containing products; in conjunction with chronic opioid use, because it contains an opioid antagonist; and during or within 14 days of taking monoamine oxidase inhibitors (MAOIs) (30).

Liraglutide (3.0 mg)

Liraglutide is a GLP-1 receptor agonist that was approved in 2010 at doses up to 1.8 mg once daily as an adjunct to diet and exercise for treatment of hyperglycemia in type 2 diabetes (30). In 2014, liraglutide 3.0 mg was approved specifically for chronic weight management, as an adjunct to reduced-calorie diet and increased physical activity (30). GLP-1 receptors, located in the hypothalamus and several other areas of the brain, are involved in appetite regulation and increase satiety (30). Liraglutide 3.0 mg is administered as a once-daily, subcutaneous injection without regard to timing of meals (30). A gradual dose escalation schedule, included in the prescribing information, is recommended to reduce the chances of gastrointestinal adverse effects (30). Liraglutide 3.0 mg should not be used in combination with other GLP-1 receptor agonists or insulin (30). Additionally, it should be discontinued if 4% weight loss is not achieved within 16 weeks of initiation or if it is not tolerated, because efficacy at lower doses has not been established (30).

Data on 1-year weight change with liraglutide 3.0 mg are summarized in Table 6 (30). Efficacy data are also available for individuals receiving 2.4-mg or 3.0-mg doses of liraglutide over a 2-year period (101).

Data for individuals receiving 2.4 mg or 3.0 mg over a 2-year time-frame were pooled and compared with data from individuals receiving orlistat (120 mg) (101). Mean weight loss in the liraglutide 2.4/3.0 mg group was 3.0 kg greater than that in the orlistat group at 2 years (P < 0.001), and significantly greater proportions of individuals lost >5% body weight (52% vs. 29%, respectively; P <0.001 for liraglutide 3.0 mg vs. orlistat) and >10% body weight (26% vs. 16%, respectively; P = 0.04 for liraglutide 2.4/3.0 mg vs. orlistat) (101).

Summaries of common adverse reactions, contraindications, and warnings and precautions included in the prescribing information for liraglutide 3.0 mg are presented in Tables 7–9 (30). In clinical trials, discontinuation due to an adverse event was reported for 9.8% and 4.3% of individuals receiving liraglutide 3.0 mg or placebo, respectively (30). The adverse events that most often led to discontinuation of liraglutide were nausea, vomiting, and diarrhea (30).

Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2 (30). This is because in rodent studies, liraglutide caused thyroid C-cell tumors, but it is not clear whether these results are relevant to humans or if liraglutide can cause C-cell tumors in people (30). Accordingly, patients should be counseled to report symptoms of thyroid tumors (e.g., mass in the neck, dysphagia, and persistent hoarseness) to their healthcare provider (30). Adults receiving liraglutide 3.0 mg for the management of obesity should also be monitored for signs and symptoms of pancreatitis, hypoglycemia, renal impairment, increased resting heart rate, and depression. If pancreatitis is suspected, appropriate management should be initiated, liraglutide 3.0 mg should be discontinued, and it should not be restarted if pancreatitis is confirmed (30). Because the risk of hypoglycemia may be increased when liraglutide 3.0 mg is used with insulin secretagogues (e.g., sulfonylureas), decreasing the insulin secretagogue dose should be considered (30). Liraglutide 3.0 mg should also be discontinued if patients experience a sustained increase in resting heart rate or suicidal thoughts or behaviors (30).

Summary

Research has increased the understanding of the persistent alterations in physiological and behavioral processes that contribute to weight gain and hamper weight loss. Evidence suggests that long-term pharmacotherapy for the management of obesity may modify these processes and thereby help individuals adhere to diet and exercise regimens, to lose more weight, and to maintain weight loss. Agents recently approved for long-term weight management offer more options for safe and effective interventions that are appropriate to individual health status, clinical situations, tolerances, and preferences, and new clinical practice guidelines for the pharmacological management of obesity provide recommendations to guide therapy. In addition, development of other agents that target obesity-promoting pathways may lead to more alternatives to address the pathophysiology of obesity in the near future. By providing patients with as many alternatives as possible, clinicians can increase the probability that their patients will be able to identify a combination of interventions that can help them manage overweight and obesity.

Conclusion

To manage obesity as a chronic disease, clinicians should be prepared to:

• Employ an array of interventions to help patients face the physiological and behavioral challenges of weight loss

• Provide ongoing and adaptable treatment to support the successful achievement of long-term weight and health goals.

Several reliable sets of clinical practice guidelines and algorithms for the management of adult obesity have been developed to provide clinicians with practical guidance when helping patients try and accomplish this goal. They are based on similar general principles, but differ somewhat in context and/or scope. However, considered together, they provide reasonably comprehensive direction for developing and implementing appropriate and individualized treatment regimens for adult obesity.

Current recommendations agree that identifying the need for treatment is the first step in managing adult obesity. BMI is recognized as a reasonable and acceptable measure to screen for the possibility of increased health risk attributed to obesity and the need to provide treatment. Before proceeding with treatment, though, it is important to assess for the risk, presence, and severity of obesity-associated complications. This is particularly true if the BMI is ≥25 but ≤30 kg/m² , because the presence of complications is relevant to the indication for pharmacotherapy in patients with BMI 27–29.9 kg/m² . Weight loss is appropriate and is indicated for individuals with BMI ≥ 30 kg/m² , even if they are otherwise healthy, because it is likely that they will eventually develop complications as a consequence of their weight. However, more aggressive weight loss therapy may be warranted in patients with obesity and complications. In addition, clinicians should assess and address potential factors that contribute to overweight and obesity, such as use of pharmacotherapies for a variety of indications (e.g., depression and pain management) that may promote weight gain.

Once it has been determined that treatment for obesity is indicated and that a person is ready to initiate therapy, the provider should work with that individual to develop an appropriate, patient-centered treatment plan. The principal goals of obesity management— improvement in body weight and composition, health, and quality of life—are achieved through interventions that help patients lose and maintain weight. Sustained weight loss of 5%-10% yields significant health benefits and is recommended as an initial goal. When setting weight loss goals, clinicians should be aware of patients’ weight loss expectations, which may be overly ambitious, and should be prepared to explain the health advantages of modest weight loss and to describe the efforts that will be required to achieve weight loss goals. Although modest weight loss can result in clinically important improvements in obesity disease status, greater weight loss can provide even greater health gains and may be needed to improve certain weight-related complications. Patients willing to work to lose more should certainly not be discouraged from doing so.

Interventions currently available for the management of adult obesity include comprehensive lifestyle management, pharmacotherapy, and bariatric surgery. Comprehensive lifestyle management is the cornerstone of obesity treatment, whereas pharmacotherapy and bariatric surgery are adjunct therapies that are indicated for use in combination with lifestyle management. More intensive approaches, namely intensive lifestyle management and/or adjunct therapies, can be employed to yield greater therapeutic results or to help individuals maintain weight loss long term. However, more intensive therapies, particularly adjunct approaches, are associated with greater risk of adverse events. For each patient, the potential benefit of reducing obesity-associated risk should be evaluated against the risk associated with the intervention. Obesity staging resources, such as the EOSS, the American Association for Clinical Endocrinologists/ACE framework for diagnosis of obesity, and the Cardiometabolic Disease Staging system may guide clinicians in characterizing disease severity as part of the risk-to-benefit assessment that is necessary for determining a patient-appropriate treatment regimen.

Comprehensive lifestyle management is indicated and appropriate for all individuals who need to lose weight. It consists of a reduced-calorie diet, increased physical activity, and behavioral intervention to develop the skill set to implement reduced caloric intake and increased caloric expenditure. Current treatment recommendations provide guidance regarding goals for caloric reduction and activity levels, but they do not stipulate the use of specific diet and exercise plans. In fact, current recommendations indicate that multiple diet and exercise plans can lead to successful weight loss, and selection of a treatment regimen should be based largely on patient preference. With regard to behavioral intervention, certain strategies have been associated with successful weight loss, such as self-monitoring and frequent contact with a trained interventionist. Recent advances in technology, as well as increased understanding of effective obesity management approaches, have increased the availability of means to implement these strategies, including electronic delivery of personalized interventions and tools for self-monitoring. In addition to working with patients to identify weight loss goals and dietary approaches, clinicians should be prepared to direct patients to available options for comprehensive lifestyle management so that each patient can identify an approach that will work for them.

For individuals who are unable to reach and maintain weight loss and/or health goals with comprehensive lifestyle management, adjunct use of pharmacotherapy and/or bariatric surgery may be an option. Treatment with weight loss medications or bariatric surgery generally produces greater weight loss and sustains that weight loss for a longer period of time than that achieved by lifestyle intervention alone. However, adjunct therapies are associated with greater risk of adverse effects than lifestyle management, and for this reason, they are reserved for individuals with more severe disease or patients with weight-related complications who will derive greater benefits from weight loss. In general, pharmacotherapy is indicated and recommended as an appropriate option for individuals with BMI ≥ 30 kg/m² or with BMI ≥ 27 kg/m² who have weight-associated complications; bariatric surgery may be an option for individuals with more severe disease, indicated by BMI ≥ 40 kg/m² or BMI ≥ 35 kg/m² and weight-associated complications. Bariatric surgery requires referral to a qualified surgeon; thus, clinicians should be prepared to refer their patients to qualified surgeons and centers, if appropriate. By comparison, pharmacotherapy is indicated for a larger subgroup of individuals with overweight or obesity, and it is accessible for use by more clinicians.

Since 2012, four pharmacological agents have been approved for long-term weight management, significantly increasing the available alternatives. Currently approved medications for long-term weight management are all from different therapeutic classes and act in different ways to address physiological and behavioral processes that contribute to obesity and to decrease food intake. Clinicians should be aware of common adverse effects, differences in dosing, and limitations regarding use in specific populations in order to appropriately advise patients of their options and educate them regarding their therapeutic choices. Additionally, clinicians should recognize that there is variability in individual responses to weight loss agents. Medications should be used at the lowest effective dose, and patients should be monitored regularly for efficacy and adverse effects. If a patient does not experience significant therapeutic benefit from one agent, it should be discontinued to avoid unnecessary medication exposure, and a different agent may be considered. As research continues, the pool of available, and potentially complementary, agents that address the pathophysiology of obesity is expected to increase, providing clinicians and patients with even more therapeutic options.

Editorial note: The AACE’s Comprehensive Diabetes Management Algorithm 2013 Consensus Statement is cited in this supplement as an authoritative source of recommendations for the management of obesity (4). As this supplement was going to print, the AACE/ACE Comprehensive Diabetes Management Algorithm 2015, with the current AACE and ACE recommendations for management of obesity and overweight, was in press (102). A prepress version of the 2015 algorithm, available on the AACE website, has incorporated medications approved by the FDA in 2014 for long-term weight management; however, unlike the 2013 version, it was not accompanied by a consensus statement (3,102). Other recent publications from AACE/ACE that address management of adult obesity include a position statement on diagnosis of obesity as a chronic disease (22) and 2015 AACE/ACE clinical practice guidelines for the management of diabetes (103).

Patient and Provider Perspectives: Addressing Barriers and Identifying an Individualized Plan

Case summary—Mrs. Green

• 32 years old

• Hypertension, prediabetes, and polycystic ovary syndrome (PCOS)

• Referred for weight loss consultation by primary care physician— patient would like to lose weight to help with conception

• Current medications

  • •
    Paroxetine—for depression
  • •
    Propranolol—for hypertension
• Vital statistics and laboratory results for this visit

  • •
    Height: 66 in (165.1 cm)
  • •
    Weight: 210 lb (95.3 kg)
  • •
    BMI: 35 kg/m²
  • •
    Blood pressure: 130/80 mm Hg
  • •
    Total cholesterol: 202 mg/dl
  • •
    Low-density lipoprotein cholesterol: 120 mg/dl
  • •
    High-density lipoprotein cholesterol: 50 mg/dl
  • •
    Triglycerides: 160 mg/dl
  • •
    Fasting blood glucose: 121 mg/dl
  • •
    Glycated hemoglobin: 5.8%
• Other considerations

  • •
    Diet

    • •
      Eats out about twice per week
    • •
      “Foodie” who loves to cook
    • •
      Has a hard time resisting delicious foods
  • •
    Physical activity

    • •
      Administrative assistant
    • •
      Walks her dog twice per day
  • •
    Strong family history of obesity (father and sister—many cousins)
  • •
    Weight loss history

    • •
      Overweight status beginning in childhood
    • •
      Slow, steady weight gain over her adult life
    • •
      11% weight loss before her wedding (3 years ago) with Jenny Craig program using meal replacements and food and exercise diary
    • •
      Has never participated in group counseling
    • •
      Has never taken prescription weight loss medications, but has taken over-the-counter supplements without much success

Expert clinical perspectives

Mrs. Green is presenting to discuss obesity management, suggesting that she is willing to start treatment. The information provided indicates that Mrs. Green has a BMI of 35 kg/m² , confirming that obesity management is appropriate. Mrs. Green already has several obesity-related complications, including hypertension, prediabetes, PCOS, and depression, indicating that more aggressive therapy is appropriate. Additional assessment is not absolutely necessary to confirm the need for treatment in this case, because a BMI ≥ 30 kg/ m² is associated with increased risk of obesity-related complications.

The provided information also indicates several factors that may have contributed to her difficulty with maintaining long-term weight loss. Review of her medications indicates that she is taking paroxetine and a beta-blocker, agents known to be associated with weight gain. She also has a sedentary job, eats out rather frequently, has difficulty avoiding tempting foods, and has a strong family history of obesity. However, she has previously experienced successful weight loss using meal replacements and a food diary.

Agreeing on a weight loss goal is one of several steps toward determining an appropriate treatment approach. It is important to determine what Mrs. Green is willing to do to lose weight (e.g., use meal replacements, participate in an intensive lifestyle management program, and take a weight loss medication). It is also important to explain the potential benefits of modest weight loss. This discussion may include observations such as:

• A larger weight loss goal (e.g., >20 lb) is ambitious and may not be necessary to obtain some health benefits; sustained weight loss of 5%-10% (11–21 lb) could lead to improved health, including prevention of type 2 diabetes

• A slightly larger weight loss goal of 10%-15% could induce ovulation and address one of the health problems that prompted her referral for obesity treatment

• Counseling regarding the effort required to achieve a more ambitious goal may be necessary, if that is what she would like to pursue.

In addition to agreeing on a weight loss goal and identifying an appropriate therapeutic intervention for weight loss, clinicians should also help patients remove barriers to weight loss. Optimizing medication regimens by selecting agents that do not lead to weight gain and/or promote weight loss may help individuals achieve their weight loss goals. Therefore, for Mrs. Green, a fundamental approach may be to replace her antidepressant and beta-blocker with alternatives that are not associated with weight gain (i.e., bupropion and an angiotensin-converting enzyme inhibitor).

Mrs. Green qualifies for adjunctive treatments—both pharmacotherapy and surgery—to help her with this weight loss attempt. The next case will review the principles of applying these tools to the lifestyle intervention approach; however, for Mrs. Green, the selected strategy should be one that recognizes the chronic nature of the disease, the value of achieving better health through weight loss, and the importance of life-long weight management approaches. So, whatever weight loss strategy is negotiated between the physician and Mrs. Green regarding an initial weight loss attempt, they both need to agree to and should be committed to a long-term relationship for weight management.

Patient and Provider Perspectives: Long-term Management—Adjusting the Strategy

Case summary—Mr. White

• 49 years old

• Referred by primary care provider for significant weight regain following laparoscopic adjustable gastric banding (LAGB) 5 years ago

• Current medications

  • •
    Metformin (2,000 mg/day)—for type 2 diabetes
  • •
    Hydrochlorothiazide (50 mg/day)—for hypertension
  • •
    Lisinopril (30 mg/day)—for hypertension
  • •
    Atorvastatin (80 mg/day)—for dyslipidemia
  • •
    Fish oil capsules
  • •
    Aspirin (81 mg/day)
• Vital statistics and laboratory results for this visit

  • •
    Height: 70 in (190.5 cm)
  • •
    Weight: 401 lb (181.9 kg)
  • •
    BMI: 50 kg/m²
  • •
    Blood pressure: 128/88 mm Hg
  • •
    Total cholesterol: 176 mg/dl
  • •
    Low-density lipoprotein cholesterol: 110 mg/dl
  • •
    High-density lipoprotein cholesterol: 35 mg/dl
  • •
    Triglycerides: 155 mg/dl
  • •
    Fasting blood glucose: 130 mg/dl
  • •
    Glycated hemoglobin: 8.0%
• Weight loss history

  • •
    Obesity in childhood
  • •
    Lost 100 lb on very low calorie liquid diet ≈ 10 years ago
  • •
    LAGB 5 years ago—lost 80 lb but has had significant regain since
  • •
    Lowest postsurgery outcomes (after losing 80 lb)

    • •
      Weight: 320 lb
    • •
      BMI: 40 kg/m²

Expert clinical perspectives

Mr. White has achieved very large weight losses several times in his adult life using intensive lifestyle approaches and adjunct therapies. Most recently, he lost 80 lb following LAGB, but in the 5 years since surgery, he has regained all of the weight he lost. His medication list indicates that he is being treated for several obesity-related complications, including type 2 diabetes, hypertension, and dyslipidemia.

Weight regain following bariatric surgery can be a major hurdle. Re-evaluation by a surgeon should be considered. Conversion of the LAGB to another procedure (i.e., gastric sleeve and gastric bypass) may be a good option for this patient. However, bariatric surgery is indicated as an approach to be used adjunct to lifestyle management; thus, it would also be appropriate to reinforce behavioral intervention and possibly identify alternative means to help the patient adhere to his diet and exercise plans.

The addition of pharmacotherapy may also be an appropriate option to help the patient adhere to diet. None of the weight loss medications currently approved for long-term use in the United States are specifically contraindicated for patients who have undergone bariatric surgery (30), and Mr. White has previously experienced successful weight loss with medication. Mr. White is being treated with metformin for type 2 diabetes. Weight loss and/or negative energy balance associated with weight loss medications may increase the risk of hypoglycemia for patients who take antidiabetic medications, particularly insulin secretagogues; thus, it may be advisable to instruct Mr. White to monitor his blood glucose more frequently at the start of the weight loss effort. Considerations specific to each medication are described later (30).

Orlistat is contraindicated in patients who have chronic malabsorption syndrome, which may occur following bypass types of bariatric surgery, but not gastric band or gastric sleeve. It may also increase gastrointestinal events in combination with a high-fat diet (>30% of total daily calories from fat). In Mr. White’s case, he must be counseled about the gastrointestinal side effects of the drug and the necessity of adhering to a low-fat diet before initiating orlistat.

There are no specific contraindications to the use of lorcaserin other than pregnancy and a warning/precaution regarding the potential risk of serotonin syndrome in combination with other serotonergic agents. It would be important to determine whether Mr. White is taking any of these agents, either in prescription or supplement form. He has previously taken fenfluramine, which has been associated with valvular heart disease, as has dexfenfluramine. Discontinuation of lorcaserin is recommended if signs or symptoms of valvular heart disease develop, but the prescribing information for this drug does not advise echocardiography to assess valvulopathy prior to initiating lorcaserin.

Phentermine/topiramate ER is contraindicated for use during or within 14 days of taking MAOIs, a history of glaucoma or hyper-thyroidism, but none of these apply for Mr. White. The phentermine component of this medication mandates monitoring heart rate in all patients, and especially those with cardiac or cerebrovascular disease. Although Mr. White does not have established CVD, he has multiple CVD risk factors; so, this warning/precaution is particularly relevant for him. Before prescribing this agent, important counseling points for patients might include potential taste disturbance with carbonated beverages, paresthesia, and assessing a history of kidney stones, as topiramate can increase risk for these events.

Naltrexone ER/bupropion ER is contraindicated in uncontrolled hypertension, history of seizures, chronic opioid use, or within 14 days of an MAOI. Although Mr. White’s hypertension is controlled, recommended monitoring of blood pressure and heart rate should occur in the first weeks of prescribing this agent. It would also be important to confirm that Mr. White is not taking any of the other agents that are contraindications to prescribing. Furthermore, this combination should not be prescribed to patients taking bupropion for depression or smoking cessation, although the combination may be a good choice for patients with depression. Additionally, he should also be asked about history of seizure disorder and use of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs, because bupropion lowers the seizure threshold. Clinicians should be aware that there are multiple drug interactions that can impact naltrexone ER/bupropion ER use (i.e., MAOIs, drugs metabolized by CYP2D6, CYP2B6 inhibitors and inducers, drugs that lower seizure threshold, and dopaminergic drugs). Before prescribing, the provider should counsel Mr. White about the importance of a slow dose escalation over 4 weeks, to minimize gastrointestinal side effects.

Before considering initiation of liraglutide 3.0 mg, Mr. White should be asked about a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, because these infrequent conditions are contraindications to the use of liraglutide 3.0 mg. There is also a potential increase in the risk of pancreatitis with liraglutide 3.0 mg; so, Mr. White should be asked about his history of pancreatitis, gallstones, alcoholism, and hypertriglyceridemia, and he should be informed of the signs and symptoms of pancreatitis if he initiates liraglutide 3.0 mg. Gastrointestinal adverse effects are common with liraglutide 3.0 mg, which may be particularly relevant in a patient who has had bariatric surgery. The effects may be limited by slow titration, and they generally decrease over time. However, because gastrointestinal adverse events and hypovolemia may lead to renal impairment, patients should inform their clinician if they experience severe symptoms. There are no specific drug interactions with liraglutide 3.0 mg, but absorption of oral medications may be affected by delayed gastric emptying.

TABLE 8.

Contraindications to use of medications approved for long-term weight management in the United States

Agent	Contraindicationsa
Orlistat	Pregnancy Chronic malabsorption syndrome Cholestasis
Lorcaserin	Pregnancy
Phentermine/topiramate ER	Pregnancy (REMS) Glaucoma Hyperthyroidism During or within 14 days of taking an MAOI
Naltrexone ER/bupropion ER	Pregnancy Uncontrolled hypertension Seizure disorders; anorexia nervosa or bulimia; abrupt discontinuation of alcohol, benzodiazepines, barbiturates, antiepileptic drugs Use of other bupropion-containing products Chronic opioid use During or within 14 days of taking an MAOI
Liraglutide 3.0 mg	Pregnancy Personal or family history of MTC or patients with MEN 2

ER, extended release; MAOI, monoamine oxidase inhibitor; MEN 2, multiple endocrine neoplasia syndrome type 2; MTC, medullary thyroid carcinoma; REMS, Risk Evaluation and Mitigation Strategy.

^aKnown hypersensitivity to the agent or any component of the product is included for all agents.