Continuing Education Activity

Obesity, a metabolic disease characterized by excessive adipose tissue, is a global epidemic affecting individuals of all ages. Classified by body mass index (BMI), it poses significant health risks, including diabetes, hypertension, hyperlipidemia, arthritis, sleep apnea, and cancer. Given its chronic nature and associated morbidity and mortality, prompt diagnosis and treatment are essential.

This activity will cover updates on recent advancements in pharmacologic therapies, focusing on their efficacy not only in weight loss but also in managing diabetes and improving cardiovascular health. The interprofessional approach to evaluating and treating obesity will be highlighted, emphasizing the importance of lifestyle modifications, medication, and, when necessary, bariatric surgery. Overall, clinicians will acquire valuable insights into the latest strategies for addressing obesity and its related health issues, enabling them to enhance patient care and outcomes.

Objectives:

• Identify individuals at risk for obesity-related complications based on comprehensive assessments of BMI, medical history, and associated comorbidities.
• Screen patients for suitability and eligibility for pharmacologic treatment, considering contraindications, previous medical history, and risk factors.
• Implement evidence-based pharmacologic interventions as part of a multidisciplinary approach to manage obesity, integrating medications into a comprehensive treatment plan.
• Coordinate long-term care plans, ensuring continuity and addressing challenges related to weight maintenance and potential side effects of pharmacologic interventions.

Introduction

Obesity is a pervasive chronic disease that continues to rise in prevalence globally, affecting not just adults but also adolescents and children. It has reached epidemic proportions and is now recognized as a significant health crisis.[1]

Epidemiological studies have defined obesity using the body mass index (BMI), calculated by dividing a person's weight in kilograms by the square of their height in meters. This method enables the stratification of obesity-related health risks within populations. A BMI exceeding 30 kg/m² is considered diagnostic for obesity and is further subclassified into class 1 (30 to 34.9 kg/m²), class 2 (35 to 39.9 kg/m²), and class 3, known as morbid obesity (≥40 kg/m²).

The primary approach to addressing obesity involves promoting weight loss through behavioral therapy, encompassing dietary changes, and adopting a healthy lifestyle with regular physical activity. Weight loss significantly reduces cardiovascular risk factors, aids disease prevention, and enhances self-esteem and overall functionality. While significant weight loss produces benefits in overall mortality, moderate weight loss (5%-10%), achievable through lifestyle modifications and medications, has been shown to significantly improve various conditions, including type 2 diabetes, hypertension, dyslipidemia, cardiovascular disease, nonalcoholic fatty liver disease, osteoarthritis, cancer, and sleep apnea.[2][3][4]

In addition to these measures, given the challenges associated with weight loss and its maintenance, evidence-based pharmacologic therapy is often deemed necessary to achieve a more effective and sustained response in managing obesity. Healthcare providers are essential in engaging in a shared decision-making process with patients, carefully considering the risks and benefits. This collaborative approach ensures the selection of the most appropriate pharmacotherapy that aligns with the patient's profile. 

When these methods prove ineffective, or if there is an urgent need for weight loss and pharmacotherapy has not yielded the desired results, bariatric surgery can be considered. Bariatric surgery has demonstrated significant improvements in morbidity and mortality. Notably, patients who have previously failed to engage in a weight loss program or refuse assistance in a behavioral program are at a high risk of relapse following bariatric surgery. Therefore, surgical intervention may not be the recommended course of action in such cases.

Issues of Concern

This activity aims to assess the existing evidence regarding currently available weight loss medications and examine substances that lack proven benefits or could be harmful, leading to their discontinuation. 

Obesity is a widely discussed topic, with a growing body of literature exploring the effectiveness of multiple compounds in its treatment. However, limited evidence supports either the endorsement or cessation of various substances and dietary supplements. Consequently, patients persist in buying over-the-counter compounds, unaware that some can be potentially harmful. 

Clinicians must caution patients about the potential risks associated with weight-loss supplements and carefully monitor those who use them. The conclusions drawn from a 2015 review regarding some of these supplements are outlined below:

• Green tea, Garcinia cambogia, conjugated linoleic acid, and chitosan exhibited no significant impact on weight loss, indicating that healthcare professionals should not endorse their use.

• Data on the effectiveness of chromium, Gambisan, Hoodia gordonii, and Cynanchum auriculatum are inconclusive. Therefore, clinicians should refrain from recommending their use due to the lack of evidence and the potential risk of harm.[5]

• Human chorionic gonadotropin (hCG) has been promoted as a potential weight loss therapy; however, clinical trials do not support its efficacy. Several randomized trials have demonstrated that hCG injections or pills, when combined with a very low-calorie diet (500 kcal/d), are no more effective than a placebo in treating obesity.[6] The weight loss effect is solely correlated to caloric restriction. Notably, very low-calorie diets are not sustainable in the long term compared to conventional diets because people tend to regain weight rapidly upon discontinuing such diets, and their impact on other aspects of health remains unclear. 

• Sibutramine was withdrawn from the US and European markets in 2010 following the Sibutramine Cardiovascular Outcomes (SCOUT) trial, which revealed a 16% increase in cardiovascular events in the medication group (11.4% versus 10% in the placebo). The Food and Drug Administration (FDA) determined that the risks outweighed the benefits. Notably, the study population included individuals aged 55 years or older who were overweight or obese and had a history of cardiovascular disease or type 2 diabetes mellitus, along with one additional cardiovascular risk factor.[7] In some countries, sibutramine is still prescribed to patients who do not meet any of the above criteria but under strict supervision and regulation.

• Lorcaserin, another regulated weight-loss medication, was withdrawn in February 2020. This decision followed a safety clinical trial involving 12,000 patients, which revealed a higher incidence of various types of cancer compared to the placebo group (7.7% versus 7.1% of patients), with the most common cancers being pancreatic, colorectal, and lung cancer. The FDA has not suggested any specific cancer screening for individuals previously on lorcaserin apart from age-appropriate screening protocols.

Clinical Significance

Sustained weight loss is rarely achievable solely through decreased food intake and increased energy expenditure due to counteractive adaptive biological responses.[8][9] Decreases in energy expenditure rates and increases in appetite following weight loss are linked to hormonal changes that encourage weight regain. 

Despite the challenges these adaptive mechanisms pose hindering sustained weight loss, the recommendation remains that all individuals adopt a healthy, well-balanced eating pattern. Ideally, this should be supervised, coupled with maintaining a regular physical activity routine of at least 30 to 60 minutes of aerobic activity on most days of the week. This approach aids in achieving weight and fat loss, improving cardiometabolic parameters, and supporting long-term weight maintenance.[10]

Nonpharmacologic Therapy

Lifestyle intervention is paramount. Before starting weight loss drug therapy, it is important to establish a lifestyle intervention program, preferably under the close supervision of a dietitian, with long-term follow-up akin to that in extended trials.[11][12] While discussing various lifestyle interventions is beyond the scope of this article, which focuses on medication therapy, it is important to note that pharmacologic therapy should be considered only after optimizing all nonpharmacologic approaches.

Dietary adherence is essential for weight loss, regardless of the chosen diet. A study comparing various types of diets found that the outcomes were directly proportional to the level of adherence exhibited by participants.[13] 

Very low-calorie diets can provide faster initial weight loss; however, the body's hormonal adaptation proves challenging to sustain long-term. Following a dietary plan that maintains a negative calorie balance in the long term is essential. Initiating medication therapy can help overcome the stagnation often observed after the initial months of diet and lifestyle intervention. 

Intermittent fasting dietary patterns can be considered a viable alternative, although studies have shown inconsistent efficacy. In a 1-year trial with 100 individuals with obesity, 3 groups were compared: alternate-day fasting (patients alternated 25% of total energy consumed on fasting days and 125% on free days) versus caloric restriction (ingesting 75% of total energy needs daily) versus nonintervention control. After 6 and 12 months, mean weight loss was comparable for individuals in the alternate fasting group (-6.8% [95% CI, -9.1% to -4.5%] and -6.0% [95% CI, -8.5% to -3.6%, respectively]) and the daily constant calorie restriction group (-6.8% [95% CI, -9.1% to -4.6%] and -5.3% [95% CI, -7.6% to -3.0%], respectively), when compared to the control group, indicating similar efficacy.[14]

Regardless of the diet or lifestyle program, continuous surveillance and follow-ups are essential. As obesity is a chronic disease with adaptative mechanisms, ongoing monitoring is mandatory to ensure better long-term outcomes. 

Exercise is vital in maintaining a negative calorie balance by increasing energy expenditure through physical activity and aiding in weight loss. A 2017 study highlighted that aerobic and anaerobic exercises combined prove more efficient for weight loss than either type of exercise in isolation.[15][16] The recommended guideline suggests engaging in approximately 30 minutes or more of exercise, 5 to 7 days a week, to prevent weight gain and enhance cardiovascular health in adults.[17] 

Behavior therapy is crucial in assisting patients with long-term changes in their eating habits. This approach involves modifying and monitoring food intake, adapting physical activity, and controlling environmental stimuli that trigger binge eating. Individuals are aided in developing healthier eating behaviors and sustaining long-lasting lifestyle changes. 

Pharmacologic Therapy

Initiating approved weight loss medications can be beneficial to sustain the positive effects of weight loss following lifestyle changes. This is particularly important if a struggle to maintain weight loss or if weight regain occurs. Pharmacologic therapy can also be considered alongside initiating a weight loss program, following a thorough discussion of the risks and benefits with the patients. 

Drug therapy can be considered for individuals with a BMI greater than 30 kg/m or a BMI of 27 to 29.9 kg/m in the presence of weight-related complications. This is especially applicable for patients who have been unable to achieve their weight loss goals (at least 5% of total body weight in 3 to 6 months) despite undergoing comprehensive lifestyle intervention. Notably, initiating drug therapy should always be coupled with the continuation of behavioral and lifestyle changes. Without this combination, medications typically yield low success rates.[18][19]

Approved medications facilitate weight loss by decreasing appetite and hunger, increasing satiety, and reducing caloric absorption or intake. Nevertheless, achieving long-term weight maintenance and overcoming the physiologic trend of regaining weight remains a significant challenge.

When considering the initiation of pharmacologic therapy, an individualized approach is necessary, factoring in the patient's comorbidities, preferences, insurance coverage, and costs. Generally, single agents are preferred over combination therapy. However, different medications can be combined to enhance the response, provided the clinician carefully evaluates safety and interaction profiles.[20]

In clinical studies of weight loss medications, a 5% to 10% reduction in body weight has traditionally been considered significant. This percentage aligns with the FDA's recommendations in trials and is linked to notable clinical improvements in metabolic risk profiles.[21] Additionally, secondary weight loss outcomes in these trials have examined the proportion of individuals achieving a 10% or greater weight loss and changes in weight from baseline.[21] 

Obesity medication therapy goals must be realistic to prevent frustration and treatment discontinuation. The focus should be on short-term and long-term weight reduction, preventing weight gain, improving health parameters, and managing side effects.[22] When starting weight loss therapy, it is crucial to emphasize that drug responses and side effects can vary significantly among patients. Moreover, patients should be informed that reaching a plateau after initial weight loss is common, and if drug treatment is interrupted, weight regain can be expected.

Semaglutide

Marketed under Ozempic, Rybelsus, and Wegovy, semaglutide is the latest long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA) approved by the Food and Drug Administration (FDA) for obesity treatment. It has shown significant weight loss benefits in patients with and without diabetes, along with improvements in glycemic control. While oral and injectable forms are FDA-approved for diabetes treatment and have demonstrated weight loss effects, only the subcutaneous preparation has received FDA approval specifically for obesity treatment.[15]

Several studies have demonstrated the effectiveness of semaglutide in promoting weight loss among individuals who are overweight or obese, irrespective of whether they have type 2 diabetes.

In the STEP 1 trial, 1961 adults without diabetes and with obesity (BMI ≥30 kg/m2 or ≥27 kg/m2 with at least 1 weight-related comorbidity) participated in a randomized controlled trial. Patients were assigned to 68 weeks of therapy with weekly subcutaneous 2.4 mg semaglutide or placebo. Individuals in the semaglutide group experienced a significant weight loss of 15.3 kg compared to 2.6 kg in the placebo group. The estimated treatment difference was 12.7 kg, 95% CI -13.7 to -11.7 kg. More patients in the semaglutide group had weight loss greater than or equal to 5 (86.4% versus 31.5%), greater than or equal to 10 (69.1% versus 12.0%), and greater than or equal to 15 (50.5% versus 4.9%) compared to the placebo group.[15]

In the STEP 2 trial, over 1200 patients with type 2 diabetes and obesity were randomized to receive weekly semaglutide doses of 1 mg and 2.4 mg and compared to a placebo. The estimated treatment difference for semaglutide 2.4 mg (-9.6%) versus placebo (-3.4%) was −6.2 percentage points (95% CI −7·3 to −5·2; p<0·0001).[23]

Semaglutide shares a similar side effect profile with other GLP-1 agonist agents, including symptoms such as nausea and vomiting. Patients are advised to report any persistent or severe side effects to their healthcare professional promptly to ensure proper guidance and adjustment of the treatment plan if necessary.

• Dosing

  • The injectable formulation of semaglutide includes subcutaneous weekly injections, starting with an initial dose of 0.25 mg for 4 weeks, followed by incremental increases every 4 weeks (0.5, 1.17, 2.4 mg) until reaching the maximum tolerated dose.
  • In patients with type 2 diabetes, glycemic levels should also be monitored before titration, and dosing of other concomitant hypoglycemic agents should be adjusted to prevent hypoglycemia.

• Contraindication

  • Individuals with a personal history of pancreatitis or a personal or familial history of medullary thyroid cancer or multiple endocrine neoplasia (MEN) 2A or 2B should avoid semaglutide. Patients should be educated about the symptoms of pancreatitis or gallbladder pathologies.

Similar to other GLP-1 agonists, semaglutide has also been shown to reduce major cardiovascular events in adults with type 2 diabetes and established cardiovascular disease or chronic kidney disease.[24]

Liraglutide

Liraglutide was the first GLP-1RA to receive approval for treating obesity in patients without diabetes. Subsequently, in 2021, Semaglutide became the second GLP-1RA to be approved for obesity treatment, extending its use to all patients without requiring a diabetes diagnosis.

Glucagon-like peptide (GLP-1), an incretin peptide secreted by the gut after oral food intake, plays a significant role. It inhibits gastric emptying and glucagon release while inducing glucose-dependent insulin release from the pancreas's beta cells. The GLP-1RAs are considered a second or third option in treating type 2 diabetes when glycemic control is not achieved. Particularly beneficial for patients with diabetes who are overweight or obese, GLP-1RAs, along with sodium-glucose cotransporter 2 (SGLT2) inhibitors, are ideal due to their proven weight loss effects. Notably, in patients without diabetes, the use of SGLT2 inhibitors for weight loss is still off-label. 

For obesity treatment, the GLP-1RAs are approved at higher doses than those recommended for diabetes treatment. They are approved for obesity treatment in adults with a BMI greater than or equal to 30 kg/m or with a BMI greater than or equal to 27 kg/m when at least 1 weight-related comorbidity (such as hypertension, type 2 diabetes, dyslipidemia, osteoarthritis) is present. Liraglutide, approved for obesity, has a daily dose of 3 mg, although an initial dose of 1.2 mg can yield weight loss and can be escalated based on tolerability. Semaglutide, approved for obesity, comes in a convenient 2.4 mg once-weekly dosage. Often, patients achieve weight loss below the maximum dose, experiencing fewer side effects and maintaining adequate glucose control. 

Randomized controlled trials have demonstrated liraglutide's efficacy in diabetes management and weight loss. Multiple studies have shown sustained weight loss and additional cardiovascular benefits over a maximum duration of 2 years. 

In a 20-week study involving 564 patients, liraglutide at 4 different daily doses (1.2, 1.8, 2.4, and 3 mg) showed dose-dependent weight loss compared to placebo or open-label orlistat, with weight losses of 5.8 kg and 3.8 kg more than placebo and orlistat, respectively. These results were consistent in a 2-year extension study, where patients on higher doses (2.4 mg and 3.0 mg) maintained a weight loss of 7.8 kg at the end of the study (total n=92 patients on the higher doses). Notably, liraglutide 3.0 mg also substantially reduced body fat by 15.4% while preserving lean tissue, which decreased by only 2.0%. Moreover, the prevalence of prediabetes and metabolic syndrome was reduced by 52% and 59%, respectively, after 2 years, accompanied by improved blood pressure and lipid levels.[25]

In a 56-week trial involving 3731 patients with a BMI greater than or equal to 30 kg/m or greater than or equal to 27 kg/m with dyslipidemia or hypertension, liraglutide 3 mg was compared with a placebo. The results demonstrated a mean weight loss of 8.0 kg versus 2.6 kg in the placebo group. Additionally, liraglutide improved several cardiometabolic risk factors, glycated hemoglobin (HgbA1C) levels, and quality of life.[26]

The LEADER trial showed that liraglutide, even at a lower dose than the recommended dosage for obesity (1.8 mg versus 3 mg), reduced major cardiovascular events, including cardiovascular-related deaths, nonfatal myocardial infarction, or nonfatal stroke, in patients with type 2 diabetes.[27] However, there is currently no available cardiovascular outcome data for patients with obesity who do not have diabetes.  

The primary side effects of liraglutide are mainly gastrointestinal, including nausea and vomiting, often more pronounced at the beginning of therapy or after dose increments. The symptoms appear to be dose-dependent. Sometimes, selecting an intermediate dose that patients can tolerate while preserving the medication's positive effects may be a practical approach.

While there is an observed finding of pancreatitis, a definitive causal relationship has not been established. Furthermore, gallbladder disease can predispose to cholelithiasis, and persistent nausea and vomiting can lead to dehydration if the medication is not discontinued.[27] Liraglutide has demonstrated an association with malignant medullary carcinoma in rodent trials; however, this correlation remains unproven in humans. 

• Dosing

  • Liraglutide is administered subcutaneously, starting with an initial dose of 0.6 mg daily for 1 week, followed by weekly increment increases of 0.6 mg until reaching the recommended dose of 3 mg.
  • While many patients cannot tolerate the highest dose, they can still experience benefits at lower dosages within their maximum tolerance level.

• Contraindications 

  • Several other GLP-1 receptor agonists with similar responses in glucose control, weight loss, and cardiovascular benefits have entered the market. However, these medications have not obtained approval for treating overweight or obese patients without diabetes.
  • Researchers have not studied the medication's effects during pregnancy, making it contraindicated in pregnant individuals. It is also not recommended for patients with a personal or family history of medullary thyroid cancer or MEN 2A or 2B. 

Semaglutide and liraglutide were compared in a randomized controlled trial (STEP 8) which included 338 adults with a BMI greater than or equal to 30 kg/m² (or ≥27 kg/m² with ≥1 weight-related comorbidity) assigned to once-weekly subcutaneous semaglutide 2.4 mg or placebo), or once-daily subcutaneous 3.0 mg liraglutide, or placebo. At the end of 68 weeks, participants in the semaglutide group demonstrated greater weight loss than the liraglutide group (-15.8% versus -6.4%; treatment difference -9.4% [95% CI -12.0 to -6.8]). In contrast, the weight change in the placebo group was -1.9 percent. Additionally, the semaglutide group exhibited a higher percentage of individuals achieving 10%, 15%, or 20% or more weight loss [28].

Orlistat

Orlistat functions by inhibiting pancreatic lipases, disrupting fat digestion in the gut. Consequently, fat molecules are not fully hydrolyzed and remain unabsorbed. The extent of weight loss correlates with the calories lost through fecal fat excretion, representing up to a 30% reduction in calorie intake on an average diet.

Several studies, including randomized control trials and meta-analyses, have demonstrated the efficacy of orlistat.[29][30] In a meta-analysis of 12 trials, the orlistat group exhibited a mean weight loss of 8%, in contrast to 5% in the placebo group, even with comparable behavioral interventions.[31] Furthermore, subjects were able to sustain their weight loss with continuous therapy for up to 24 to 36 months.  

In the Xendos study, 3304 patients who were overweight were randomly assigned to orlistat or placebo. Notably, 21% of these patients had impaired glucose tolerance. Over the first year, researchers observed a substantial disparity between groups, with the orlistat group experiencing an 11% reduction from baseline, compared to 6% in the placebo group. Although this gap narrowed during the subsequent 3 years of the trial, the orlistat group maintained a 6.9% reduction from baseline, while the placebo showed a 4.1% reduction. Despite the diminished difference by the study's end, patients in the orlistat group had a lower incidence of diabetes than the placebo group (6.2% versus 9%). In trials involving patients with diabetes, orlistat also led to greater weight loss and lower HgbA1c levels at 1 year compared to the placebo groups.[32]

Additional benefits of orlistat have been observed in various studies. A systematic review highlighted a decrease in systolic and diastolic blood pressure in individuals taking prlistat compared to placebo (with a weighted difference of -2.5 and -1.9 mm Hg, respectively).[33] Moreover, in a multicenter trial, orlistat demonstrated improvements in serum lipid values, including a 5% to 10% reduction in low-density lipoprotein (LDL) cholesterol in patients treated with orlistat and a low-fat diet over 48 weeks from baseline.[34]

• Dosing:

  • The recommended dose is 120 mg, taken 3 times daily, accompanying each meal.
  • Patients are strongly advised to take a daily multivitamin at bedtime to compensate for the reduced absorption of fat-soluble vitamins associated with chronic orlistat use.
  • This medication is available over the counter in many countries, including the United States. 

• Contraindications:

  • Patients can utilize orlistat for up to 4 years in obesity treatment. If therapy extends beyond this period, it is essential to discuss it with the patient, informing them about the absence of extended studies. 
  • The medication has not undergone studies in pregnant individuals and should not be considered for patients with chronic malabsorption, cholestasis, or calcium oxalate stones.

Commonly observed side effects of orlistat are gastrointestinal, including abdominal cramps, increased flatulence, and fecal incontinence. These effects are more prevalent early in its use and often diminish when patients adhere to a low-fat diet (<30%) without compromising weight loss benefits.[35] Although the FDA recorded 13 instances of severe liver injury, establishing a direct cause has proven challenging due to patients concurrently taking other medications and having underlying medical conditions that could contribute to such incidents. However, individuals using orlistat should understand the need to contact their healthcare professional if signs or symptoms of liver injury occur. There is no heightened risk of cholelithiasis, cardiovascular issues, or psychiatric events associated with orlistat usage. 

Orlistat's mechanism of fat fecal excretion can impair the levels of fat-soluble vitamins (A, D, E, K) and beta-carotene. Additionally, it can prolong the international normalized ratio (INR) and prothrombin time in patients taking warfarin by reducing vitamin K levels, requiring a reduction of warfarin dosage and careful monitoring.[36]

Fat malabsorption leads to the binding of enteric calcium with fat excreted in stools. Consequently, intestinal oxalate becomes more accessible for absorption and subsequent excretion in the urine. Excessive free oxalate can accumulate in the renal parenchyma, potentially resulting in acute nephrocalcinosis and acute kidney injury.[37]

Combination therapies

Given the chronic nature of obesity requiring prolonged treatment and the potential side effects associated with various medications, combination therapies have been suggested as a more practical approach. This involves using lower doses of 2 medications, allowing 1 drug to offset the potential side effects of the other while maximizing their efficacy. 

Phentermine-topiramate combination

In 2012, the FDA approved the combination of phentermine-topiramate for adults with a BMI of 30 kg/m² or greater or with a BMI of 27 kg/m² or less with at least 1 weight-related comorbidity (eg, hypertension, diabetes, dyslipidemia) to be used alongside reduced dietary caloric intake for weight loss. It is not advisable for patients with a high cardiovascular risk due to a potential increase in heart rate; however, a 2-year trial did not show an elevated mortality compared to the placebo group. Long-term data on mortality is currently unavailable. This combination can be considered as the initial option in obesity treatment, especially for patients who did not tolerate or failed liraglutide or orlistat, particularly those with binge eating disorder. 

In the Conquer trial involving 2487 patients, there was a change in body weight of -1.4 kg in the placebo group versus -8.1 in the phentermine-topiramate (7.5/46 mg) group after 56 weeks.[38] In the extension study (Sequel) that followed patients for an additional 52 weeks, patients on the low dose of phentermine-topiramate achieved a mean weight loss of 9.6 kg versus 2.1 kg in the placebo group after 108 weeks from the original baseline.[39] Although the weight loss in the second year was less pronounced, most participants could maintain their weight loss, while the placebo group experienced a slight increase in body weight. Notably, all individuals were simultaneously participating in a lifestyle modification program. 

Participants in the phentermine-topiramate group exhibited improved cardiovascular and metabolic variables and a lower incidence of diabetes than the placebo group. The combination remained tolerated over 108 weeks, with adverse events occurring more frequently in the initial trial phase. 

The most commonly reported side effects of the medication include paraesthesias, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Patients in the medication-treated groups experienced a slight reduction in blood pressure, accompanied by a slight increase in heart rate of 1.3 and 1.7 bpm for low and high doses, respectively, versus 0.4 in the placebo group. However, there were no reported adverse events related to the increase in heart rate. 

Regarding psychiatric side effects, there was no increase in severe suicidal ideation or behavior among participants during the 108 weeks of observation. Reports of dose-dependent anxiety-related adverse events were noted (3.1%, 6.5%, and 9.5% for placebo, 7.5/46 mg, and 15/92 mg arms, respectively), but they were mostly of mild severity.

• Dosing: There are 4 different fixed drug combinations for the phentermine-topiramate combination.

  • The starting dose is 3.75/23 mg for 14 days, which should then be increased to the recommended 7.5/46 mg dose.
  • If, after 12 weeks of treatment, a 3% loss of baseline body weight does not occur, the recommendation is to escalate the dose to 11.25/69 mg for another 14 days and then to 15/92 mg after that.
  • If <5% of body weight is achieved after 12 weeks on the highest dose, the medication should be gradually discontinued to avoid withdrawal symptoms from topiramate.

• Contraindications:

  • The phentermine-topiramate combination is contraindicated during pregnancy due to teratogenicity, posing a risk of orofacial clefts in infants exposed to the medication during the first trimester of pregnancy. Therefore, it is mandatory to obtain a pregnancy test before initiating the drug in childbearing-age females and then monthly after that.
  • Additionally, the combination should not be used in patients with hyperthyroidism or acute angle glaucoma and is not recommended for individuals who have taken monoamine oxidase inhibitors in the past 14 days.
  • Caution is advised in patients with a history of kidney stones due to the increased risk related to topiramate. 

Recommended monitoring includes:

• Heart rate assessment at every visit.

• Regular screening for suicidal behavior and ideation, with discontinuation of the drug if symptoms develop.

• Monitoring for visual disturbances, especially acute myopia, and signs of increased intraocular pressure.

• Evaluation of cognitive function due to potential disturbances in attention or memory caused by topiramate.

• Periodic checks of electrolytes and creatinine before and during treatment, as topiramate inhibits carbonic anhydrase enzyme, predisposing individuals to acidosis, although significant acidosis has not been reported in the trials.

Phentermine can also serve as a monotherapy in the short-term treatment of obesity. It is FDA-approved for use over a few weeks, coupled with exercise, behavioral modification, and caloric restriction, specifically for patients with a BMI of 30 kg/m or greater or 27 kg/m2 or less in the presence of additional risk factors, such as controlled hypertension, diabetes, hyperlipidemia.

Phentermine suppresses appetite and induces early satiety, commonly prescribed as monotherapy. A notable study, conducted in 1968 over 36 weeks, assessed continuous and intermittent administration of phentermine, resulting in more significant weight loss than the placebo (-12.2 and -13.0 kg for continuous and intermittent use, respectively, versus -4.8 kg in the placebo group).[40]

In the category of sympathomimetic drugs, sibutramine was withdrawn from the US and European markets in 2010 following the SCOUT study, which revealed a 16% rise in the incidence of cardiovascular events (comprising nonfatal heart attack, nonfatal stroke, resuscitation after cardiac arrest, and cardiovascular death) among patients treated with the drug compared to the placebo group (more details on section "issues of concern"). 

Naltrexone-bupropion

Although no head-to-head studies comparing this combination therapy and phentermine-topiramate are available, the outcomes from published trials suggest its lower efficacy compared to the previously mentioned treatment. Consequently, it is not recommended as the primary pharmacologic therapy for managing obesity.

The naltrexone-bupropion combination serves as a viable option, particularly beneficial for individuals aiming to quit smoking while addressing weight concerns. Although this combination's precise weight loss mechanism is not fully understood, it is theorized that they synergistically impact hunger centers in the hypothalamus and the mesolimbic dopamine circuit.

Bupropion, functioning as a weak dopamine and norepinephrine reuptake inhibitor, stimulates pro-opiomelanocortin (POMC) production and the release of alpha-MSH and beta-endorphin, an endogenous opioid, in vitro. Alpha-MSH activates the melanocortin-4 receptor (MC4R), contributing to reduced food intake, increased energy expenditure, and subsequent weight loss. However, with sustained bupropion intake, beta-endorphin's down-regulatory effect on POMC cells is initiated through binding to the inhibitory mu-opioid receptor. Naltrexone, an opioid antagonist, counteracts this effect by blocking the mu-opioid receptor, disrupting the beta-endorphins inhibitory feedback on POMC cells.[41][42]  

FDA approved the combination drug in September 2014 for weight loss, diet, and exercise for patients with a BMI of 30 kg/m or greater or 27 kg/m or less with at least 1 weight-related comorbidity. This medication offers a valuable option for individuals struggling with obesity, particularly those seeking a comprehensive approach to weight management.

In a multicenter randomized trial, the combination resulted in a -6.1% reduction in body weight versus -1.3% in the placebo group, with only 50% of participants completing the 56 weeks of treatment. While mean weight loss was greater with combination therapy than with placebo, there were significant increases in mean blood pressure and heart rate reductions in the placebo group (-2.1/2.8 versus 0.2/-0.4 mmHg and -0.1 versus 1.5 beats per minute).

The naltrexone-bupropion combination commonly causes nausea, headache, and constipation. The FDA advises monitoring patients for suicidal behavior and ideation, the risk of seizure due to bupropion lowering the seizure threshold, an increase in blood pressure and heart rate, hepatotoxicity observed with naltrexone exposure, and angle-closure glaucoma.

Clinicians are advised to refrain from prescribing the drug to patients with high cardiovascular risk due to the observed increase in heart rate and blood pressure. A cardiovascular safety trial was interrupted in the initial phase due to a breach of confidentiality, but preliminary data showed reduced cardiovascular events. However, the issue remains controversial due to the lack of study completion. The medication received approval with a warning for increased blood pressure and heart rate, but the cardiovascular risk was inconclusive.[43]

• Dosing: 

  • The initial dose is 1 tablet daily containing 8 mg of naltrexone and 90 mg of bupropion.
  • If tolerated, the dose should increase to 1 tablet twice daily after the first week and 2 tablets twice daily in the fourth week.

• Contraindications:

  • Pregnancy
  • Uncontrolled hypertension
  • Seizure disorder
  • Eating disorder
  • Use of other bupropion-containing products
  • Chronic opioid use
  • Use of monoamine oxidase inhibitors in the previous 14 days

Enhancing Healthcare Team Outcomes

To date, several pharmacotherapy options for obesity exist, although they are not a definitive solution to the problem. While they have demonstrated positive outcomes in enhancing cardiometabolic parameters, some may have undesirable side effects. Predicting individual responses and tolerance remains challenging.

Several anti-obesity drugs have been withdrawn from the market due to significant side effects. Currently, the only approved drugs in the US are orlistat, liraglutide, semaglutide, phentermine-topiramate, phentermine alone, and bupropion-naloxone. Sibutramine was withdrawn more than ten years ago, and lorcaserin was removed more recently due to an increased risk of various types of cancer.

The currently approved medications lack long-term safety studies. Given the lack of longer-term studies, significant adverse effects, limited efficacy, and warnings over the safety of medicines, healthcare practitioners need to emphasize that obesity is a chronic condition requiring lifelong monitoring. This should be accompanied by a low-calorie diet, regular physical activity, and the support of a multidisciplinary team, including a dietician, primary care provider, endocrinologist, and, when necessary, psychiatrist or therapist. Bariatric surgery should also be considered as an option for patients with refractory obesity who have exhausted other medical therapies or who face complications from obesity. Evaluation by a behavioral therapist is crucial to rule out binge eating disorder or other compulsive disorders. 

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References

1.

Global BMI Mortality Collaboration, Di Angelantonio E, Bhupathiraju ShN, Wormser D, Gao P, Kaptoge S, Berrington de Gonzalez A, Cairns BJ, Huxley R, Jackson ChL, Joshy G, Lewington S, Manson JE, Murphy N, Patel AV, Samet JM, Woodward M, Zheng W, Zhou M, Bansal N, Barricarte A, Carter B, Cerhan JR, Smith GD, Fang X, Franco OH, Green J, Halsey J, Hildebrand JS, Jung KJ, Korda RJ, McLerran DF, Moore SC, O'Keeffe LM, Paige E, Ramond A, Reeves GK, Rolland B, Sacerdote C, Sattar N, Sofianopoulou E, Stevens J, Thun M, Ueshima H, Yang L, Yun YD, Willeit P, Banks E, Beral V, Chen Zh, Gapstur SM, Gunter MJ, Hartge P, Jee SH, Lam TH, Peto R, Potter JD, Willett WC, Thompson SG, Danesh J, Hu FB. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet. 2016 Aug 20;388(10046):776-86. [PMC free article: PMC4995441] [PubMed: 27423262]

2.

Torgerson JS, Sjöström L. The Swedish Obese Subjects (SOS) study--rationale and results. Int J Obes Relat Metab Disord. 2001 May;25 Suppl 1:S2-4. [PubMed: 11466577]

3.

Abdelaal M, le Roux CW, Docherty NG. Morbidity and mortality associated with obesity. Ann Transl Med. 2017 Apr;5(7):161. [PMC free article: PMC5401682] [PubMed: 28480197]

4.

Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, Ryan DH, Still CD., Endocrine Society. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015 Feb;100(2):342-62. [PubMed: 25590212]

5.

Esteghamati A, Mazaheri T, Vahidi Rad M, Noshad S. Complementary and alternative medicine for the treatment of obesity: a critical review. Int J Endocrinol Metab. 2015 Apr;13(2):e19678. [PMC free article: PMC4386228] [PubMed: 25892995]

6.

Bosch B, Venter I, Stewart RI, Bertram SR. Human chorionic gonadotrophin and weight loss. A double-blind, placebo-controlled trial. S Afr Med J. 1990 Feb 17;77(4):185-9. [PubMed: 2405506]

7.

James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Shepherd GM, Rode RA, Renz CL., SCOUT Investigators. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010 Sep 02;363(10):905-17. [PubMed: 20818901]

8.

Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, Gallagher D, Mayer L, Murphy E, Leibel RL. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest. 2005 Dec;115(12):3579-86. [PMC free article: PMC1297250] [PubMed: 16322796]

9.

Rosenbaum M, Hirsch J, Gallagher DA, Leibel RL. Long-term persistence of adaptive thermogenesis in subjects who have maintained a reduced body weight. Am J Clin Nutr. 2008 Oct;88(4):906-12. [PubMed: 18842775]

10.

Mabire L, Mani R, Liu L, Mulligan H, Baxter D. The Influence of Age, Sex and Body Mass Index on the Effectiveness of Brisk Walking for Obesity Management in Adults: A Systematic Review and Meta-Analysis. J Phys Act Health. 2017 May;14(5):389-407. [PubMed: 28169568]

11.

Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol. 2015 Nov;3(11):866-75. [PMC free article: PMC4623946] [PubMed: 26377054]

12.

Look AHEAD Research Group. Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, Crow RS, Curtis JM, Egan CM, Espeland MA, Evans M, Foreyt JP, Ghazarian S, Gregg EW, Harrison B, Hazuda HP, Hill JO, Horton ES, Hubbard VS, Jakicic JM, Jeffery RW, Johnson KC, Kahn SE, Kitabchi AE, Knowler WC, Lewis CE, Maschak-Carey BJ, Montez MG, Murillo A, Nathan DM, Patricio J, Peters A, Pi-Sunyer X, Pownall H, Reboussin D, Regensteiner JG, Rickman AD, Ryan DH, Safford M, Wadden TA, Wagenknecht LE, West DS, Williamson DF, Yanovski SZ. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013 Jul 11;369(2):145-54. [PMC free article: PMC3791615] [PubMed: 23796131]

13.

Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA. 2005 Jan 05;293(1):43-53. [PubMed: 15632335]

14.

Trepanowski JF, Kroeger CM, Barnosky A, Klempel MC, Bhutani S, Hoddy KK, Gabel K, Freels S, Rigdon J, Rood J, Ravussin E, Varady KA. Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial. JAMA Intern Med. 2017 Jul 01;177(7):930-938. [PMC free article: PMC5680777] [PubMed: 28459931]

15.

Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF., STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002. [PubMed: 33567185]

16.

Villareal DT, Aguirre L, Gurney AB, Waters DL, Sinacore DR, Colombo E, Armamento-Villareal R, Qualls C. Aerobic or Resistance Exercise, or Both, in Dieting Obese Older Adults. N Engl J Med. 2017 May 18;376(20):1943-1955. [PMC free article: PMC5552187] [PubMed: 28514618]

17.

Piercy KL, Troiano RP, Ballard RM, Carlson SA, Fulton JE, Galuska DA, George SM, Olson RD. The Physical Activity Guidelines for Americans. JAMA. 2018 Nov 20;320(19):2020-2028. [PMC free article: PMC9582631] [PubMed: 30418471]

18.

Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014 Jan 01;311(1):74-86. [PMC free article: PMC3928674] [PubMed: 24231879]

19.

Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu FB, Hubbard VS, Jakicic JM, Kushner RF, Loria CM, Millen BE, Nonas CA, Pi-Sunyer FX, Stevens J, Stevens VJ, Wadden TA, Wolfe BM, Yanovski SZ, Jordan HS, Kendall KA, Lux LJ, Mentor-Marcel R, Morgan LC, Trisolini MG, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC, Tomaselli GF., American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. 2014 Jun 24;129(25 Suppl 2):S102-38. [PMC free article: PMC5819889] [PubMed: 24222017]

20.

Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, Nadolsky K, Pessah-Pollack R, Plodkowski R., Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITYEXECUTIVE SUMMARYComplete Guidelines available at https://www.aace.com/publications/guidelines. Endocr Pract. 2016 Jul;22(7):842-84. [PubMed: 27472012]

21.

Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, Loomba R, Camilleri M, Singh S. Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis. JAMA. 2016 Jun 14;315(22):2424-34. [PMC free article: PMC5617638] [PubMed: 27299618]

22.

Kaplan LM, Golden A, Jinnett K, Kolotkin RL, Kyle TK, Look M, Nadglowski J, O'Neil PM, Parry T, Tomaszewski KJ, Stevenin B, Lilleøre SK, Dhurandhar NV. Perceptions of Barriers to Effective Obesity Care: Results from the National ACTION Study. Obesity (Silver Spring). 2018 Jan;26(1):61-69. [PubMed: 29086529]

23.

Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, Rosenstock J, Shimomura I, Viljoen A, Wadden TA, Lingvay I., STEP 2 Study Group. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021 Mar 13;397(10278):971-984. [PubMed: 33667417]

24.

Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsbøll T., SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-1844. [PubMed: 27633186]

25.

Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, Niskanen L, Rasmussen MF, Rissanen A, Rössner S, Savolainen MJ, Van Gaal L., NN8022-1807 Investigators. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond). 2012 Jun;36(6):843-54. [PMC free article: PMC3374073] [PubMed: 21844879]

26.

Wadden TA, Hollander P, Klein S, Niswender K, Woo V, Hale PM, Aronne L., NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond). 2013 Nov;37(11):1443-51. [PubMed: 23812094]

27.

Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB., LEADER Steering Committee. LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. [PMC free article: PMC4985288] [PubMed: 27295427]

28.

Rubino DM, Greenway FL, Khalid U, O'Neil PM, Rosenstock J, Sørrig R, Wadden TA, Wizert A, Garvey WT., STEP 8 Investigators. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA. 2022 Jan 11;327(2):138-150. [PMC free article: PMC8753508] [PubMed: 35015037]

29.

Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004 Jan;27(1):155-61. [PubMed: 14693982]

30.

Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, Hilton L, Suttorp M, Solomon V, Shekelle PG, Morton SC. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med. 2005 Apr 05;142(7):532-46. [PubMed: 15809465]

31.

Leblanc ES, O'Connor E, Whitlock EP, Patnode CD, Kapka T. Effectiveness of primary care-relevant treatments for obesity in adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2011 Oct 04;155(7):434-47. [PubMed: 21969342]

32.

Kelley DE, Bray GA, Pi-Sunyer FX, Klein S, Hill J, Miles J, Hollander P. Clinical efficacy of orlistat therapy in overweight and obese patients with insulin-treated type 2 diabetes: A 1-year randomized controlled trial. Diabetes Care. 2002 Jun;25(6):1033-41. [PubMed: 12032111]

33.

Siebenhofer A, Jeitler K, Horvath K, Berghold A, Posch N, Meschik J, Semlitsch T. Long-term effects of weight-reducing drugs in people with hypertension. Cochrane Database Syst Rev. 2016 Mar 02;3:CD007654. [PubMed: 26934640]

34.

Yancy WS, Westman EC, McDuffie JR, Grambow SC, Jeffreys AS, Bolton J, Chalecki A, Oddone EZ. A randomized trial of a low-carbohydrate diet vs orlistat plus a low-fat diet for weight loss. Arch Intern Med. 2010 Jan 25;170(2):136-45. [PubMed: 20101008]

35.

Padwal R, Li SK, Lau DC. Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev. 2004;2003(3):CD004094. [PMC free article: PMC8078201] [PubMed: 15266516]

36.

MacWalter RS, Fraser HW, Armstrong KM. Orlistat enhances warfarin effect. Ann Pharmacother. 2003 Apr;37(4):510-2. [PubMed: 12659605]

37.

Singh A, Sarkar SR, Gaber LW, Perazella MA. Acute oxalate nephropathy associated with orlistat, a gastrointestinal lipase inhibitor. Am J Kidney Dis. 2007 Jan;49(1):153-7. [PubMed: 17185156]

38.

Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, Day WW. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011 Apr 16;377(9774):1341-52. [PubMed: 21481449]

39.

Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, Schwiers M, Day WW, Bowden CH. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012 Feb;95(2):297-308. [PMC free article: PMC3260065] [PubMed: 22158731]

40.

Munro JF, MacCuish AC, Wilson EM, Duncan LJ. Comparison of continuous and intermittent anorectic therapy in obesity. Br Med J. 1968 Feb 10;1(5588):352-4. [PMC free article: PMC1984840] [PubMed: 15508204]

41.

Billes SK, Greenway FL. Combination therapy with naltrexone and bupropion for obesity. Expert Opin Pharmacother. 2011 Aug;12(11):1813-26. [PubMed: 21689063]

42.

Greenway FL, Whitehouse MJ, Guttadauria M, Anderson JW, Atkinson RL, Fujioka K, Gadde KM, Gupta AK, O'Neil P, Schumacher D, Smith D, Dunayevich E, Tollefson GD, Weber E, Cowley MA. Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring). 2009 Jan;17(1):30-9. [PubMed: 18997675]

43.

Nissen SE, Wolski KE, Prcela L, Wadden T, Buse JB, Bakris G, Perez A, Smith SR. Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial. JAMA. 2016 Mar 08;315(10):990-1004. [PubMed: 26954408]

Disclosure: Lorenna Rodrigues Silva Sombra declares no relevant financial relationships with ineligible companies.

Disclosure: Catherine Anastasopoulou declares no relevant financial relationships with ineligible companies.