Challenging obesity: Patient, provider, and expert perspectives on the roles of available and emerging nonsurgical therapies.

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/m 2 , more than doubled in that timeframe, increasing from 11.1% to 26.9% ( 11 ). Rates of severe obesity, defined as BMI ≥ 40 kg/m 2 , 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.

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 ). 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 ). 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/m 2 or with BMI ≥ 27 kg/m 2 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. Pharmacotherapy is recommended as an adjunct to comprehensive lifestyle management for individuals with BMI > 30 kg/m 2 or with BMI ≥ 27 kg/m 2 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) 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. 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. 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 ). 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) ( 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 ). 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 ). 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 ). 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 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 5% body weight (52% vs. 29%, respectively; P 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 ). 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.

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) 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/m 2 • 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% Height: 70 in (190.5 cm) Weight: 401 lb (181.9 kg) BMI: 50 kg/m 2 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/m 2 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/m 2 Weight: 320 lb BMI: 40 kg/m 2 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.

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. 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/m 2 , because the presence of complications is relevant to the indication for pharmacotherapy in patients with BMI 27–29.9 kg/m 2 . Weight loss is appropriate and is indicated for individuals with BMI ≥ 30 kg/m 2 , 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/m 2 or with BMI ≥ 27 kg/m 2 who have weight-associated complications; bariatric surgery may be an option for individuals with more severe disease, indicated by BMI ≥ 40 kg/m 2 or BMI ≥ 35 kg/m 2 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 ).