Obesity in adults: Drug therapy

INTRODUCTION — A number of medications are approved by the US Food and Drug Administration for the treatment of overweight or obesity. It is essential that the medications are used in conjunction with healthy eating, physical activity, and behavior modification, as medication usage without such changes are generally ineffective over the long term.

The decision to initiate drug therapy in people with obesity should consider the risks and benefits of weight loss medications [1-5]. The goals of drug therapy should be clear, along with an awareness that most medications require long-term use to maintain weight loss. This topic will review drug treatments for patients with overweight and obesity. Other treatments for the management of overweight and obesity are discussed elsewhere. (See "Obesity in adults: Overview of management".)

GOALS OF THERAPY — Treatment for individuals with overweight or obesity should focus on long-term weight reduction and improvement in overall health [6].

●Reduce weight and maintain weight loss – Contemporary clinical trials evaluating the efficacy of antiobesity medications have demonstrated 5 to 22.5 percent weight loss when added to lifestyle modification [7-10]. We consider a weight loss medication to be effective if weight loss exceeds 4 to 5 percent of baseline weight after three months on a therapeutic dose of medication and is maintained at this level.

Upon initiation of antiobesity medication, we communicate several important messages to patients. First, not every drug works for every patient; individual responses vary widely. Second, when the maximal therapeutic effect is achieved, weight loss plateaus or ceases. This does not mean the drug has "stopped" working. It simply means that further weight loss will require additional strategies. Finally, if drug therapy is discontinued, weight regain is expected.

Many factors make it difficult to achieve and maintain weight loss, including weight loss-induced changes in energy expenditure and hormonal mediators of appetite, all of which favor weight regain [11,12]. Given these factors and the fact that obesity is a chronic disease, we recommend using antiobesity medications long term for weight loss maintenance if they are well tolerated and have yielded clinically meaningful weight loss (>5 percent).

●Improve health status – Weight loss treatment may also improve physical function, comorbidities, and sense of well-being. A weight loss of 5 to 10 percent can significantly impact cardiovascular risk, including decreasing blood pressure and reducing the risk of progression from prediabetes to diabetes; reduce osteoarthritis-related knee pain; and improve obesity-related hepatic steatosis [13-17]. (See "Overview of primary prevention of cardiovascular disease", section on 'Overweight and obesity' and "Management of knee osteoarthritis", section on 'Weight loss' and "Management of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults", section on 'Weight loss'.)

Improvement in health status after weight loss is an important criterion for determining whether to continue drug therapy [18]. (See 'Monitoring' below.)

●Minimize adverse effects – We monitor side effects and tolerability to minimize the potential risks of drug therapy. We also counsel patients regarding the lack of long-term safety and efficacy data for most medications, especially for new medications, such as the glucagon-like peptide 1 receptor agonists. The longest clinical trial examining the safety and efficacy of pharmacotherapy for weight loss utilized orlistat for four years [13].

OUR APPROACH — Our approach is based on available clinical trial evidence, clinical expertise, and published guidelines [5,19,20].

Role of behavioral interventions — Our approach to weight loss starts with behavioral interventions and lifestyle changes for all patients. Thorough, compassionate counseling around healthy eating, physical activity, and health-seeking behavior is essential. Behavioral interventions should continue in those who start an antiobesity medication. (See "Obesity in adults: Overview of management", section on 'Initial treatment' and "Obesity in adults: Dietary therapy" and "Obesity in adults: Behavioral therapy" and "Obesity in adults: Role of physical activity and exercise".)

Addressing comorbidities — As part of the initial evaluation, clinicians should assess weight-related conditions. Health complications of excess weight span a wide range of body systems and include type 2 diabetes, dyslipidemia, hypertension, heart disease, obstructive sleep apnea, symptomatic osteoarthritis, hepatic steatosis, mental health disorders, and difficulty with physical function. (See "Obesity in adults: Prevalence, screening, and evaluation", section on 'Evaluation of patients with obesity' and "Overweight and obesity in adults: Health consequences".)

We prefer a holistic approach to weight management. This means prioritizing comorbidity treatments that promote weight loss or are weight neutral, when possible [1,21]. Drugs that cause weight gain should be avoided if reasonable alternatives are available [22]. Medications for diabetes, depression (table 1), and autoimmune diseases are particularly notorious for causing weight gain. For patients already on a chronic medication that promotes weight gain, we try to change to one that promotes weight loss or is weight neutral. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus" and "Major depressive disorder in adults: Approach to initial management".)

Candidates for drug therapy — Candidates for drug therapy include individuals who have not met weight loss goals (loss of at least 5 percent of total body weight at three to six months) with comprehensive lifestyle intervention and have:

●Obesity and a body mass index (BMI) ≥30 kg/m² or

●A BMI of 27 to 29.9 kg/m² plus one or more weight-related comorbidities

Given that BMI is a screening tool, a waist circumference should also be checked. This allows for confirmation of excess body fat, consistent with a diagnosis of obesity, as opposed to an elevated BMI due to higher muscle mass (see "Obesity in adults: Prevalence, screening, and evaluation"). The decision to initiate drug therapy should be individualized and weigh the risks and benefits of all treatment options (lifestyle, pharmacologic, device, surgical) and the impact of obesity on the patient's functional status, overall health, and specific medical comorbidities.

Choice of agent

Key considerations — In choosing a medication for individual patients, we consider the drug's efficacy, contraindications, side effects, availability, coverage by insurance, patient preference, and cost [23]. Because most antiobesity medications do not have generic options, they can be expensive and may not be covered by insurance. Cost/coverage is often a primary consideration in agent selection (algorithm 1) [24].

Although we prioritize efficacy in medication selection, some uncertainty exists regarding the comparative efficacy of different agents. Although network meta-analyses can estimate the relative efficacy of different agents, few head-to-head trials exist comparing individual therapies. Additionally, many trials of antiobesity medications have limitations, including short duration, high attrition rates, heterogeneity, and inadequate reporting of important clinical outcomes (eg, cardiovascular outcomes) [2].

Incretin-based therapies preferred — First-line medications for weight loss management include the glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GLP-1) dual receptor agonist tirzepatide and the GLP-1 receptor agonists semaglutide 2.4 mg and liraglutide 3 mg.

Patients without type 2 diabetes — Our selection among the incretin-based therapies tirzepatide, semaglutide, and liraglutide prioritizes medication efficacy and takes into account the presence of cardiovascular disease (CVD) [9,25-29].

●Without cardiovascular disease – We suggest tirzepatide as preferred therapy for these individuals because it is likely most effective for weight loss [30]. Subcutaneous semaglutide 2.4 mg weekly or liraglutide 3 mg daily are reasonable alternatives. We prefer semaglutide to liraglutide because of its greater efficacy and once-weekly dosing (figure 1). (See 'Preferred medications' below.)

Tirzepatide and subcutaneous semaglutide 2.4 mg appear to have superior efficacy for weight reduction compared with other agents. Tirzepatide may be more efficacious than semaglutide; however, the single comparative efficacy study compared tirzepatide with semaglutide at doses lower than those approved for chronic weight management (1.7 and 2.4 mg once weekly). As an example, in an open-label trial of over 1800 patients with diabetes, once-weekly tirzepatide (in varying doses) reduced body weight more than semaglutide 1 mg at 40 weeks (reductions of 7.6, 9.3, and 11.2 kg with 5, 10, and 15 mg tirzepatide, respectively, versus 5.7 kg with semaglutide) [25]. (See 'Dosing and monitoring' below.)

Subcutaneous semaglutide 2.4 mg results in greater weight loss than liraglutide 3 mg (figure 1). As an example, in a network meta-analysis of participants without diabetes who had a BMI ≥30 kg/m² or BMI ≥27 kg/m² with comorbidities, weekly semaglutide 2.4 mg appeared more likely to result in weight loss of ≥5 percent than liraglutide 3 mg [27]. A representative trial from the meta-analysis found that at 68 weeks, participants randomized to once-weekly subcutaneous semaglutide 2.4 mg lost more weight than those randomized to once-daily subcutaneous liraglutide 3 mg (mean weight change -15.8 versus -6.4 percent; difference -9.4 percent; 95% CI -12.0 to -6.8) [9]. We prefer semaglutide to liraglutide because of its greater efficacy and once-weekly dosing. (See 'Preferred medications' below.)

Subcutaneous semaglutide 2.4 mg also appears to have superior efficacy compared with other GLP-1 receptor agonists, phentermine-topiramate, naltrexone-bupropion, and orlistat. In a network meta-analysis, greater weight loss occurred with GLP-1 receptor agonists (mean difference [MD] of percentage body weight change -5.76; 95% CI -6.3 to -5.21) and phentermine-topiramate (MD -7.97; 95% CI -9.28 to -6.66) than with naltrexone-bupropion and orlistat [29]. Post hoc analysis found that semaglutide 2.4 mg resulted in the greatest odds of weight loss of 5 percent or more (odds ratio 9.82, 95% CI 7.09-13.61) and percentage body weight change (MD -11.41, 95% CI -12.54 to -10.27).

●With cardiovascular disease – For individuals with established CVD, we suggest once-weekly subcutaneous semaglutide 2.4 mg as the preferred therapy, especially for those who prioritize cardiovascular outcomes over weight loss [31]. Tirzepatide is a reasonable alternative in these patients, particularly those who prioritize weight loss over potential cardiovascular benefit. Liraglutide (3 mg) is an option for individuals who cannot obtain or tolerate tirzepatide or semaglutide. We discuss the different advantages of tirzepatide, semaglutide, and liraglutide and incorporate patients' priorities into the decision-making process.

We prefer subcutaneous semaglutide for individuals with CVD because it has demonstrated reductions in cardiovascular endpoints (see 'Cardiovascular benefits' below). Although tirzepatide does not yet have proven cardiovascular benefit, it is a reasonable option for those who prioritize weight loss since it appears most efficacious and the absolute cardiovascular risk reduction with semaglutide and liraglutide is modest. We prefer semaglutide or tirzepatide to liraglutide because liraglutide is less effective for weight reduction and has not been shown to reduce cardiovascular outcomes in individuals without diabetes. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

Patients with type 2 diabetes — We suggest tirzepatide or semaglutide 2.4 mg as preferred agents for treating obesity in individuals with type 2 diabetes mellitus. We use the same considerations to choose between these agents in patients with diabetes as we do for those without diabetes. As outlined above, these depend in part on the presence of CVD. (See 'Patients without type 2 diabetes' above.)

For individuals with diabetes who cannot access semaglutide 2.4 mg or tirzepatide, we use other GLP-1-based therapies that are used to treat diabetes, such as semaglutide 2 mg, dulaglutide, or liraglutide. Because these three agents have cardiovascular benefits in individuals with type 2 diabetes who also have CVD or are at high risk of CVD, some other UpToDate authors prefer them over tirzepatide for this subset of patients (see "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Choice of therapy'). The cardiovascular effects of GLP-1 receptor agonists in individuals with type 2 diabetes are discussed separately. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)

Additional options for individuals with diabetes include extended-release exenatide or oral semaglutide. However, because they are less efficacious for weight loss, we typically prefer non-GLP-1-based antiobesity medications (eg, phentermine-topiramate) over these medications unless the latter are needed for glycemic control. (See 'Alternative agents' below.)

Other GLP-1 agents, their indications, and their benefits apart from weight reduction are discussed separately. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)

Tirzepatide, semaglutide, and liraglutide may be expensive, have limited coverage by insurance, and can be difficult to obtain. Patients must be willing to perform subcutaneous injections and able to tolerate their common gastrointestinal side effects, such as nausea, vomiting, diarrhea, and constipation.

Alternatives to incretin-based therapies — For those who cannot obtain or tolerate tirzepatide, semaglutide, or liraglutide, next choice agents depend on patient comorbidities, insurance coverage, and cost. Agents with proven efficacy compared with placebo include phentermine-topiramate, naltrexone-bupropion, phentermine, and orlistat (figure 1) [7,21,32]. Dosing, efficacy, contraindications, and adverse effects for these agents are discussed subsequently. (See 'Alternative agents' below.)

●Patients without cardiovascular disease or uncontrolled hypertension – We suggest phentermine-topiramate as a preferred agent for these individuals because it is the most effective medication apart from the incretin-based medications. Naltrexone-bupropion is a reasonable alternative for long-term use and phentermine for short-term use. For individuals without insurance coverage for the combined versions of phentermine-topiramate or naltrexone-bupropion, single-agent formulations of the medications can be used (eg, topiramate and phentermine) because these are usually much less expensive. We typically reserve orlistat for individuals who cannot use any of these options. (See 'Phentermine-topiramate' below and 'Naltrexone-bupropion' below.)

Although we prioritize efficacy when selecting between these medications, a patient's individual medical conditions may also guide agent selection. As an example, individuals with migraine headaches might prefer phentermine-topiramate because topiramate is effective for migraine prophylaxis. Naltrexone-bupropion is a reasonable option for individuals who smoke, have untreated depression and obesity, and want treatment for both conditions. It may also benefit people with obesity and comorbid alcohol use disorder given naltrexone's indication for treating the latter. (See "Bulimia nervosa in adults: Pharmacotherapy".)

●Patients with cardiovascular disease or uncontrolled hypertension – We typically use orlistat or naltrexone-bupropion to treat obesity in these individuals. Naltrexone-bupropion can occasionally elevate blood pressure, and its cardiovascular safety has not been established. Phentermine (alone or in combination) can elevate the heart rate and increase blood pressure and should be avoided in those with CVD or uncontrolled hypertension. (See 'Phentermine-topiramate' below and 'Naltrexone-bupropion' below.)

Monitoring — After initiating drug therapy, we initially communicate with patients every four to six weeks to assess medication toleration and titrate doses, especially in those who are on incretin-based therapies. We often use telehealth communication and encourage patients to inform us immediately if they develop medication side effects. We typically see patients every two to three months to monitor weight and other vital signs and address side effects, including hypoglycemia in those with diabetes. Patients who are tolerating a therapeutic dose of medication and are losing weight can have less frequent follow-up.

●Weight – We initially monitor weight every two to three months. If patients do not lose 4 to 5 percent of body weight after 12 weeks of therapy (at the maximum tolerated dose), we typically discontinue the medication. In individuals who had progressive weight gain that stopped with the initiation of pharmacotherapy, we often continue that medication even if they have not lost 4 to 5 percent of body weight at 12 weeks on the maximum dose. (See 'Lack of response to initial treatment' below.)

●Heart rate and blood pressure – Individuals taking weight loss medications, particularly phentermine-topiramate, phentermine, or naltrexone-bupropion, should undergo monitoring of blood pressure and heart rate at each visit. (See 'Phentermine-topiramate' below and 'Sympathomimetic drugs for short-term use' below.)

●Blood glucose concentration in patients with diabetes – Weight loss may cause hypoglycemia in patients taking medication for diabetes, especially insulin or insulin secretagogues (eg, sulfonylureas, meglitinides). Such patients should self-monitor for symptoms of hypoglycemia and perform glucose self-monitoring at least daily during initiation and dose titration of weight loss medications, particularly with incretin-based therapies. In patients with well-controlled diabetes, we typically reduce doses of insulin, sulfonylureas, or meglitinides during the first four weeks of treatment and adjust medications further based on blood glucose values. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Contraindications and precautions'.)

●Adverse effects – We ask about adverse effects during every follow-up visit. More specific monitoring instructions depend upon the drug initiated. As examples:

•Patients taking tirzepatide, liraglutide, or semaglutide should be monitored for symptoms of gastroesophageal reflux disease, acute pancreatitis, and gallbladder disease.

•Phentermine-topiramate and naltrexone-bupropion may cause neuropsychiatric side effects, and patients taking these drugs should be monitored for depression, suicidal thoughts, or cognitive changes. We also monitor for symptoms of depression and suicidal thoughts in those taking tirzepatide, semaglutide, and liraglutide because of some case reports suggesting an association between these medications and suicidal thoughts and actions [33]. However, initial observational studies have not suggested a causal relationship [34,35].

•Hyperchloremic, non-anion gap metabolic acidosis and increases in serum creatinine have been reported in patients treated with phentermine-topiramate because topiramate is a carbonic anhydrase inhibitor. Thus, serum electrolytes (including bicarbonate) and creatinine should be measured before and approximately four weeks after initiation of this combination agent.

Duration of therapy — Obesity is a chronic medical condition, and most individuals require life-long therapy.

Discontinuation of treatment is associated with weight regain. As an example, in a trial of individuals with overweight or obesity who were initially treated with subcutaneous semaglutide 2.4 mg for 20 weeks, participants who were then randomly assigned to continue semaglutide continued to lose weight, whereas those switched to placebo experienced significant weight regain at 48 weeks (figure 2) [36]. Similar weight regain on discontinuation occurs with tirzepatide [37].

Lack of response to initial treatment — Although it is uncertain whether those who fail to respond to one drug will respond to another (or to a combination drug), we usually try a second agent. For individuals who meet surgical criteria, bariatric surgery is also an option. (See "Obesity in adults: Overview of management", section on 'Bariatric surgery' and "Bariatric surgery for management of obesity: Indications and preoperative preparation", section on 'Indications'.)

PREFERRED MEDICATIONS — The incretin peptides (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide, also called gastric inhibitory polypeptide [GIP]) are gastrointestinal peptides that stimulate glucose-dependent insulin secretion. GLP-1 also inhibits glucagon release and gastric emptying, which increases satiety during meals. GLP-1 receptor agonists also act directly in the hypothalamus to decrease appetite and increase satiety. Dual receptor agonists may be more effective than "traditional" GLP-1 receptor agonists for achieving weight loss.

GLP-1 receptor agonists were initially approved for the treatment of type 2 diabetes. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)

Tirzepatide — Tirzepatide is a dual-acting GLP-1 and glucose-dependent insulinotropic polypeptide (also called GIP) receptor agonist with substantial efficacy for weight reduction in individuals with overweight and obesity [10]. Selection between tirzepatide and other agents is discussed elsewhere. (See 'Choice of agent' above.)

Dosing and monitoring — Tirzepatide is administered by once-weekly subcutaneous injection. The starting dose is 2.5 mg once weekly for four weeks and then increased to 5 mg once weekly (table 2). The dose may be increased in 2.5 mg increments at a minimum of four-week intervals to the maximum dose of 15 mg once weekly [38]. We use the minimum dose needed to achieve the desired weight loss.

In patients with type 2 diabetes, we monitor for glycemic control and hypoglycemia, especially in those using insulin or sulfonylureas (see 'Monitoring' above). Patients with diabetic retinopathy should have slower dose titration and be monitored for progression [38].

Efficacy for weight loss — Multiple randomized trials have demonstrated substantial weight loss with tirzepatide in individuals with and without diabetes [10,26,37,39].

●A meta-analysis of six trials of 4036 participants found that tirzepatide was more effective than placebo for the treatment of overweight and obesity [30]. In an included randomized trial of over 2500 adults with obesity but without diabetes, tirzepatide 5, 10, and 15 mg resulted in more weight loss at 72 weeks than did placebo (mean percentage change in body weight -15, -19.5, -20.9, and -3.1 percent, respectively) [10].

●In the SURMOUNT-2 trial of 938 participants with obesity and type 2 diabetes, mean percentage change in body weight at 72 weeks was greater for participants randomized to 10 mg or 15 mg of tirzepatide, compared with placebo (-12.8 percent [standard error (SE) 0.6], -14.7 percent [SE 0.5], and -3.2 percent [SE 0.5], respectively) [26]. More participants on tirzepatide 15 mg than placebo had at least 5 percent weight reduction (83 percent versus 32 percent; odds ratio 8.3; 95% CI 5.7-12.3). Thirty-one percent of those randomized to tirzepatide 15 mg lost ≥20 percent body weight.

Adverse effects and contraindications

●Adverse effects – The most frequently reported adverse effects of tirzepatide are dose related and include nausea, vomiting, diarrhea, constipation, and increased heart rate [10,25]. As an example, in a large, randomized trial, tirzepatide caused higher rates of nausea (25 to 33 percent), diarrhea (19 to 23 percent), and constipation (12 to 17 percent), compared with placebo (9.5, 7.3, and 5.8 percent, respectively) [10]. Symptoms typically occurred with dose escalation and were mitigated by changes in eating patterns (eg, small, frequent meals) and/or slower dose escalation.

Due to side effects of delayed gastric emptying and the risk of food regurgitation or aspiration during anesthesia, patients undergoing elective surgery should hold tirzepatide seven days prior to surgery [33,40,41].

Patients on tirzepatide should be monitored for depressive symptoms and suicidal thoughts. (See 'Monitoring' above.)

●Contraindications – Tirzepatide is contraindicated during pregnancy [38]. Incretin-based therapies are contraindicated in those with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B because some studies found a possible increased risk of thyroid cancer with the use of GLP-1 receptor agonists [38,42,43]. However, in a subsequent cohort comprised of nationwide databases from three Scandinavian countries, GLP-1 receptor agonist use was not associated with an increased risk of thyroid cancer over a median follow-up of 3 years, compared with use of dipeptidyl peptidase 4 inhibitors [44].

Monitoring of calcitonin or thyroid ultrasounds are not recommended in those taking incretin-based therapies.

Subcutaneous semaglutide 2.4 mg — Subcutaneous semaglutide has demonstrated efficacy for weight loss in trials involving patients with and without type 2 diabetes (figure 1) [8,9,45,46]. It can also improve glycemia and lipids and has demonstrated cardiovascular benefits [8,47-49]. Selection among GLP-1-based therapies is discussed elsewhere. (See 'Choice of agent' above.)

Dosing and monitoring — Semaglutide is administered subcutaneously in the abdomen, thigh, or upper arm once weekly. The initial dose is 0.25 mg once weekly for four weeks (table 2). The dose is increased at four-week intervals (0.5, 1, 1.7, 2.4 mg) to the recommended dose of 1.7 or 2.4 mg once weekly [50]. We use the minimum dose required to achieve the desired weight loss. If dose escalation is not tolerated due to side effects (eg, nausea, vomiting), the increase in dose can be delayed by another four weeks. Patients can be maintained on the 1.7 mg dose if they have an acceptable weight loss response or cannot tolerate the 2.4 mg dose. Limited data exist regarding the efficacy of lower doses in patients without diabetes.

In patients with type 2 diabetes, we monitor for hypoglycemia and glycemic control (see 'Monitoring' above). Patients with diabetic retinopathy should also be monitored for complications and the titration slowed [50].

Efficacy for weight loss — Once-weekly subcutaneous semaglutide 2.4 mg has been shown to induce weight loss in individuals considered overweight or with obesity, with or without diabetes, in multiple randomized trials. As examples:

●In Semaglutide Treatment Effect in People With Obesity (STEP) 1, a randomized trial including 1961 adults without diabetes and a body mass index (BMI) of ≥30 kg/m² (or ≥27 with ≥1 weight-related comorbidity), participants were assigned to 68 weeks of treatment with once-weekly subcutaneous 2.4 mg semaglutide or placebo, plus lifestyle intervention [8]. Mean weight loss was greater in the semaglutide group compared with placebo (-15.3 versus -2.6 kg; 95% CI -13.7 to -11.7). More participants in the semaglutide group achieved a weight reduction of ≥5 percent (86.4 versus 31.5 percent), ≥10 percent (69.1 versus 12.0 percent), and ≥15 percent (50.5 versus 4.9 percent). More participants in the semaglutide group discontinued treatment due to gastrointestinal side effects compared with those in the placebo group (4.5 versus 0.8 percent).

The addition of a more intensive lifestyle intervention with an initial calorie-restricted diet to semaglutide treatment (STEP 3 trial) was not associated with significantly greater weight loss than a less intensive lifestyle intervention (STEP 1 trial) [8,51].

●The STEP 2 trial compared once-weekly semaglutide 1 mg and 2.4 mg with placebo in 1200 patients with type 2 diabetes mellitus and obesity [46]. Both treatment groups lost more weight compared with placebo (6.9 kg [-7 percent], -9.7 kg [-9.6 percent], and -3.5 kg [-3.4 percent], respectively), but the mean treatment difference was greatest with semaglutide 2.4 mg (-6.21 percent, 95% CI -7.28 to -5.15). (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Weight loss'.)

Cardiovascular benefits

●Cardiovascular disease – Subcutaneous semaglutide 2.4 mg has been shown to reduce major cardiovascular events in adults with established cardiovascular disease (CVD) who did not have diabetes. As an example, in the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial of 17,604 individuals with established CVD and a BMI of ≥27 kg/m², fewer cardiovascular events occurred in those randomized to subcutaneous semaglutide 2.4 mg weekly compared with placebo (6.5 versus 8 percent; hazard ratio 0.80; 95% CI 0.72-0.90) [49]. Semaglutide has also been shown to reduce CVD events in patients with type 2 diabetes mellitus, although at doses lower than those recommended for weight loss (0.5 and 1 versus 2.4 mg) [52,53].

●Heart failure with preserved ejection fraction – Semaglutide may also improve heart failure symptoms in individuals with heart failure with preserved ejection fraction (HFpEF) [54]. In a randomized trial of 529 individuals with HFpEF and obesity (BMI of ≥30 kg/m²), once-weekly semaglutide 2.4 mg produced greater improvements in heart failure symptoms, exercise function, and weight loss [55]. The role of weight loss in the treatment of heart failure is discussed separately. (See "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Obesity'.)

Adverse effects and contraindications

●Adverse effects – As with other GLP-1 receptor agonists, adverse effects are common; the major adverse effects are gastrointestinal, including nausea, vomiting, diarrhea, and constipation. In the STEP 1 trial, these adverse effects were generally mild to moderate and, for most patients, improved over time [8]. In the SELECT trial, adverse events were twice as likely to lead to permanent discontinuation of the study drug (16.6 versus 8.2 percent in the semaglutide and placebo groups, respectively; p>0.001) [49].

Uncommon, but more serious, gastrointestinal adverse effects may also occur more frequently with GLP-1 receptor agonists than with other weight loss agents. As an example, in a population-based cohort study, use of GLP-1 receptor agonists (semaglutide or liraglutide), compared with naltrexone-bupropion, was associated with a higher incidence of pancreatitis, bowel obstruction, and gastroparesis [56]. Although results were adjusted for multiple confounders, they should be interpreted with caution given the potential for unmeasured confounding between individuals who used GLP-1 receptor agonists and naltrexone-bupropion.

Due to side effects of delayed gastric emptying and the risk of food regurgitation or aspiration during anesthesia, patients undergoing elective surgery should hold semaglutide seven days prior to surgery [33,40,41].

Patients on GLP-1 receptor agonists should be monitored for depressive symptoms and suicidal thoughts. (See 'Monitoring' above.)

●Contraindications – Semaglutide is contraindicated during pregnancy and in those with a personal history of pancreatitis or a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B [50]. Monitoring of calcitonin or thyroid ultrasounds are not recommended in patients being treated with GLP-1 receptor agonists. (See 'Adverse effects and contraindications' above.)

Liraglutide — Daily subcutaneous liraglutide 3 mg is indicated for the treatment of obesity in adults with a BMI ≥30 kg/m² or ≥27 kg/m² with at least one weight-related morbidity (eg, hypertension, type 2 diabetes, dyslipidemia) [57]. Liraglutide is a chemically modified version of human GLP-1 and the first GLP-1 receptor agonist approved for the treatment of obesity. It has beneficial effects on glycemia in addition to demonstrated efficacy for weight loss [58].

Dosing and monitoring — We treat with liraglutide at the maximum dose (3 mg daily) to optimize weight loss. Liraglutide is administered subcutaneously in the abdomen, thigh, or upper arm once daily. The initial dose is 0.6 mg daily for one week. The dose is increased at weekly intervals (1.2, 1.8, 2.4, 3 mg) to the recommended dose of 3 mg (table 2) [57]. For individuals in whom side effects (eg, nausea, vomiting) limit tolerability, we use a slower dose titration and will continue liraglutide at the maximum tolerated dose if ≥4 percent weight loss is achieved by 16 weeks.

Patients with diabetes should monitor for hypoglycemia and adjust other diabetes medication as needed while on liraglutide [59] (see 'Monitoring' above). Monitoring of calcitonin or thyroid ultrasounds are not recommended in patients being treated with GLP-1 receptor agonists. (See 'Adverse events and contraindications' below.)

Efficacy for weight loss — Data from randomized trials demonstrate the efficacy of liraglutide for weight reduction and maintenance in individuals with and without diabetes [14,60-63]. Representative studies include:

●In a 56-week trial comparing liraglutide 3 mg once daily with placebo injection in 3731 patients without diabetes who had a BMI of ≥30 kg/m² or ≥27 kg/m² with dyslipidemia and/or hypertension, mean weight loss was significantly greater in the liraglutide group (-8.0 versus -2.6 kg with placebo) [62]. Liraglutide also modestly improved cardiometabolic risk factors, glycated hemoglobin (A1C), and quality of life.

The subset of individuals with prediabetes at baseline continued the trial for 160 weeks. Although only half of participants completed follow-up, the liraglutide group had greater mean weight loss (-6.1 versus -1.9 percent) and longer time to diabetes onset (99 versus 87 weeks), compared with placebo [14].

●Liraglutide is also efficacious for maintaining weight loss. As an example, a 56-week trial randomized 422 patients with obesity or overweight (BMI ≥30 kg/m² or ≥27 kg/m² with dyslipidemia and/or hypertension but without diabetes) who had lost ≥5 percent of their body weight with caloric restriction to either liraglutide 3 mg daily or placebo. A higher proportion of participants assigned to liraglutide maintained at least 5 percent weight loss (81.4 compared with 48.9 percent in the placebo group) [63]. Data demonstrating long-term (>3-year) weight reduction are scant [14].

Cardiovascular benefits — Liraglutide reduces major CVD events in adults with type 2 diabetes and pre-existing CVD, although at a lower dose than that recommended for weight loss (1.8 versus 3 mg) [64] (see "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'). Cardiovascular outcomes with liraglutide have not been studied in people with obesity who do not have diabetes.

Adverse events and contraindications

●Adverse effects – Gastrointestinal side effects, including nausea and vomiting, are common [60,62,63]. In a large clinical trial, participants receiving liraglutide 3 mg were more likely to experience nausea (40 percent) and vomiting (16 percent) than those assigned to placebo (15 and 4 percent, respectively) [62].

Other side effects include diarrhea, constipation, low blood sugar, and anorexia. Serious but less common side effects include pancreatitis, gallbladder disease, and kidney impairment. In one trial, pancreatitis, although rare, occurred more frequently with liraglutide treatment (10 cases in the liraglutide group versus 2 cases with placebo) [62]. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Adverse effects'.)

Due to side effects of delayed gastric emptying and the risk of food regurgitation or aspiration during anesthesia, patients undergoing elective surgery should hold liraglutide on the day of surgery [33,40,41].

Patients on GLP-1 receptor agonists should be monitored for depressive symptoms and suicidal thoughts. (See 'Monitoring' above.)

●Contraindications – Liraglutide is contraindicated during pregnancy and in individuals with a personal history of pancreatitis or a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B. Although rodent studies found an increased risk of benign and malignant thyroid C-cell tumors with liraglutide, this has not been confirmed in clinical trials in humans. (See 'Adverse effects and contraindications' above and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Contraindications and precautions'.)

ALTERNATIVE AGENTS — Alternative options include combination medications (eg, phentermine-topiramate and naltrexone-bupropion), drugs that alter fat digestion (orlistat), and sympathomimetic drugs (eg, phentermine). Because the regulation of food intake is controlled by several pathways, combining two drugs with different mechanisms of action could improve efficacy and tolerability compared with single-drug therapy.

Phentermine-topiramate — Phentermine-topiramate is a reasonable option for individuals without cardiovascular disease (or uncontrolled hypertension) who cannot tolerate or access glucagon-like peptide 1 (GLP-1) receptor agonists.

Combined phentermine-topiramate is indicated for adults with a body mass index (BMI) ≥30 kg/m² or with a BMI ≥27 kg/m² with at least one weight-related comorbidity (eg, hypertension, diabetes, dyslipidemia) [65]. Combining generic phentermine with generic topiramate for weight loss (each taken individually) can reduce patients' out-of-pocket costs; however, the efficacy and safety of this approach has not been established.

●Dosing and monitoring – The initial dose of phentermine-topiramate is 3.75/23 mg for 14 days, followed by 7.5/46 mg thereafter. If after 12 weeks a 3 percent loss in baseline body weight is not achieved, the dose can be increased to 11.25/69 mg for 14 days and then to 15/92 mg daily (table 2) [66]. If an individual does not lose 5 percent of body weight after 12 weeks on the highest dose, phentermine-topiramate should be discontinued. Because abrupt withdrawal of topiramate can cause seizures, we typically taper the dose by having patients take the medication every other day for one week and then stopping it [66].

We monitor for neuropsychiatric side effects, including depression, suicidal thoughts, or cognitive changes. Because of the teratogenic potential of topiramate, we typically perform a pregnancy test before starting this medication and monthly thereafter for females at risk of becoming pregnant. However, given the logistical difficulty of monthly pregnancy tests, use of this medication is typically reserved for males or females who are postmenopausal, not sexually active with males, or using highly effective contraceptives (eg, intrauterine device or tubal ligation).

Use of phentermine monotherapy is reviewed below. (See 'Sympathomimetic drugs for short-term use' below.)

●Efficacy – Combined phentermine-topiramate causes weight loss in the first year of use. As an example, a trial of 2487 adults with BMI of 27 to 45 kg/m² and two or more comorbidities found superior weight loss at one year in those randomized to combination phentermine-topiramate (7.5/46 mg or 15/92 mg) compared with placebo (8 to 10 kg versus 1.4 kg; loss of 8 to 10 percent versus 1.2 percent of baseline body weight) [67]. Only 61 percent of participants completed one year of treatment. A trial in participants with severe obesity (BMI ≥35 kg/m²) reported similar results [68].

Phentermine-topiramate can also help maintain weight loss. As an example, in an extension of the preceding trial [67], mean total weight loss at 108 weeks was significantly better with phentermine-topiramate (-9.6, -10.9, and -2.1 kg for low dose, high dose, and placebo, respectively) [15]. Phentermine-topiramate was less effective in the second year of use; although, most individuals were able to maintain weight loss.

●Adverse effects – The most common adverse events of phentermine-topiramate include dry mouth (13 to 21 versus 2 percent with placebo), constipation (15 to 17 versus 6 percent), and paresthesias (14 to 21 versus 2 percent) [67,68]. Dose-related increases in the incidence of psychiatric (eg, depression, anxiety) and cognitive (eg, disturbance in attention) adverse effects can also occur. Although blood pressure improved slightly with active therapy, there was an increase in heart rate (0.6 to 1.6 beats/min) compared with placebo.

●Contraindications – Phentermine is contraindicated in patients with coronary heart disease, uncontrolled hypertension, or hyperthyroidism because it can increase heart rate and blood pressure. It is also contraindicated in individuals with current or prior substance use disorder (table 2).

Phentermine-topiramate is contraindicated during pregnancy because of an increased risk of orofacial clefts in infants exposed to the combination drug during the first trimester of pregnancy. We advise females of childbearing potential of the medication's teratogenic risk and counsel those at risk of pregnancy to use reliable contraception.

Phentermine-topiramate is contraindicated in patients with hyperthyroidism or glaucoma and in patients who have taken monoamine oxidase inhibitors within 14 days. Because topiramate can produce kidney stones, it should be used cautiously in patients with a history of nephrolithiasis.

Clinicians who prescribe phentermine-topiramate are encouraged to enroll in a Risk Evaluation and Mitigation Strategy (REMS), which includes an online or print formal training module detailing safety information [69]. Pharmacies that dispense the drug require certification, which involves identifying a representative to oversee the REMS program and providing patients with a medication guide and brochure that details the risks of congenital anomalies.

Naltrexone-bupropion — Naltrexone-bupropion is second-line pharmacotherapy for weight loss given its lower efficacy compared with GLP-1 receptor agonists and phentermine-topiramate, twice daily dosing, and uncertainty about cardiovascular safety. Naltrexone-bupropion has greater weight loss than orlistat; however, it has more contraindications and possibly more side effects (table 2). (See 'Choice of agent' above.)

Naltrexone-bupropion is indicated in individuals with BMI ≥30 kg/m² or ≥27 kg/m² with at least one weight-related comorbidity [70]. Bupropion is a dopamine reuptake inhibitor used for the treatment of depression and smoking cessation. Naltrexone is an opioid receptor antagonist used to treat alcohol and opioid dependence. The rationale for their combination comes from animal studies in which combination therapy utilized bupropion's ability to stimulate hypothalamic pro-opiomelanocortin (POMC) neurons while simultaneously blocking opioid-mediated POMC autoinhibition with naltrexone [71]. Additional preclinical data indicated synergism of these drugs in midbrain dopamine areas to reduce food intake [72]. (See "Atypical antidepressants: Pharmacology, administration, and side effects", section on 'Bupropion' and "Pharmacotherapy for smoking cessation in adults", section on 'Bupropion' and "Opioid use disorder: Pharmacologic management", section on 'Naltrexone: Opioid antagonist'.)

●Dosing and monitoring – The initial dose is one tablet (8 mg of naltrexone and 90 mg of bupropion) daily. After one week, the dose is increased to one tablet twice daily and, by week four, to two tablets twice daily (table 2).

We monitor all individuals for suicidal thoughts and behaviors, especially adults aged 18 to 24.

●Efficacy – Compared with placebo, the combination of naltrexone-bupropion reduces weight by approximately 4 to 5 percent [73-77]. As an example, in a randomized trial of naltrexone-bupropion versus placebo, weight loss was greater in those assigned to active treatment (mean change in body weight -6 percent with naltrexone 32 mg/bupropion 360 mg versus -1.3 percent with placebo) [73]. However, only 50 percent of participants completed 56 weeks of treatment.

●Adverse effects – In clinical trials, nausea (30 versus 5 percent), headache (14 versus 9 percent), and constipation (15 versus 6 percent) occur more frequently in the naltrexone-bupropion than the placebo group [73,74]. Other adverse effects included insomnia, vomiting, dizziness, and dry mouth, occurring in 7 to 10 percent [73,74].

The cardiovascular safety of naltrexone-bupropion has not been established [78]. A randomized trial designed to assess cardiovascular outcomes of naltrexone-bupropion was terminated early due to public release of confidential interim data by the sponsor [79]. In interim analysis after 25 percent of planned events, the primary outcome (time to first major adverse cardiovascular event) had occurred in 0.8 versus 1.3 percent of patients in the placebo group (hazard ratio [HR] 0.59; 95% CI 0.39-0.90). The final analysis showed no significant difference in rates of the primary outcome but lacked precision (2.7 versus 2.8 percent; HR 0.95; 95% CI 0.65-1.38). Because the trial was terminated early, it is unclear how to interpret these data, and the cardiovascular safety remains unknown.

Although antidepressant use may increase the risk of suicide in individuals with depression, a pooled analysis of five trials including 2500 adults taking naltrexone-bupropion found no difference in depression or suicidality compared with placebo [80]. (See "Effect of antidepressants on suicide risk in adults".)

●Contraindications – Because bupropion can lower the seizure threshold, naltrexone-bupropion should be avoided in people who have seizure disorders, bulimia nervosa, or a history of alcohol withdrawal seizures. Other contraindications include pregnancy, uncontrolled hypertension, chronic opioid use, severe kidney or hepatic dysfunction, and use within 14 days of taking monoamine oxidase inhibitors [81].

Orlistat — Orlistat is a second-line agent for the treatment of obesity due to its lower efficacy and limited tolerability due to gastrointestinal side effects (figure 1). Orlistat is safe and can reduce blood pressure, lipid levels, and the risk of diabetes.

Orlistat alters fat digestion by inhibiting pancreatic lipases. Orlistat increases fecal fat excretion because fat is not completely hydrolyzed and able to be absorbed. In normal individuals eating a diet that contains 30 percent fat, orlistat causes a dose-dependent increase in fecal fat excretion, inhibiting the absorption of approximately 25 to 30 percent of calories ingested as fat. Orlistat also has demonstrated efficacy for weight loss in individuals who follow a low-fat diet (<30 percent of daily energy) [82].

●Dosing – The recommended dose of orlistat is 120 mg three times daily, during or up to one hour after a meal (table 2). A 60 mg over-the-counter version is approved and available in some countries, including the United States. Two of the 60 mg capsules are equivalent to one 120 mg capsule. Because orlistat may decrease the absorption of fat-soluble vitamins, we typically advise patients to take a multivitamin at bedtime.

●Efficacy for weight loss – Orlistat's efficacy for weight loss has been demonstrated in meta-analyses and randomized trials [13,83-94]. As an example, in a meta-analysis of 12 trials, participants randomly assigned to orlistat plus a behavioral intervention lost 5 to 10 kg (8 percent of baseline weight) compared with 3 to 6 kg in the control group (placebo plus behavioral intervention), for a mean between group difference of 3 kg (95% CI -3.9 to -2.0 kg) at 12-month follow-up [94].

Orlistat has demonstrated efficacy for weight loss for up to four years. In a four-year trial of 3305 participants with obesity, those randomized to orlistat had greater weight loss at one and four years, compared with those randomized to placebo (mean weight loss 5.8 versus 3.0 kg; p>0.001) [13].

●Effects on cardiovascular risk factors – Data from randomized trials show that orlistat reduces levels of glycosylated hemoglobin (A1C) and incident diabetes [13,89-91]. Orlistat slightly reduces blood pressure in individuals with hypertension [17]. It also improves serum lipid values, including total cholesterol, low-density lipoprotein cholesterol, and postprandial hypertriglyceridemia, more than can be explained by weight reduction alone [85,95,96].

●Adverse effects – Orlistat should not be used during pregnancy or in patients with chronic malabsorption, cholestasis, or a history of calcium oxalate kidney stones.

•Gastrointestinal – The predominant side effects of orlistat are gastrointestinal, including intestinal borborygmi and cramps, flatus, fecal incontinence, oily spotting, and flatus with discharge [91]. In a meta-analysis of nine trials, these side effects occurred in 15 to 30 percent of participants [97]. Side effects were greatest early on and subsided as participants learned to minimize fat intake.

Although severe liver injury has been reported rarely with orlistat [98], analysis of a large population-based cohort did not support a causal relationship [99]. Nevertheless, patients who take orlistat should contact their clinician if they develop itching, jaundice, pale color stools, or anorexia.

•Absorption of fat-soluble vitamins – Orlistat can decrease levels of fat-soluble vitamins (A, D, E, K) and beta-carotene, with vitamin D the most frequently affected [97]. Individuals who take warfarin and orlistat need monitoring and possible dose reduction of warfarin [100].

•Kidney – Oxalate-induced acute kidney injury has also been reported in orlistat users [101-103]. Orlistat-induced fat malabsorption may cause increased binding of enteric calcium with resultant increase in intestinal oxalate absorption and urinary oxalate excretion. Free oxalate can be deposited in the kidney parenchyma, resulting in acute kidney injury. (See "Kidney stones in adults: Epidemiology and risk factors".)

Sympathomimetic drugs for short-term use — Phentermine, benzphetamine, phendimetrazine, and diethylpropion are less used agents. They are typically used for the short-term treatment of obesity (ie, 12 weeks) because of their potential side effects, potential for abuse, limited duration of use, and regulatory surveillance. Some UpToDate experts use phentermine long term in selected patients, whereas others do not.

Sympathomimetic drugs reduce food intake by suppressing appetite and increasing energy expenditure.

Phentermine in combination with topiramate is reviewed separately above. (See 'Alternative agents' above.)

●Efficacy – Phentermine, as a single agent, has demonstrated efficacy for weight loss. As an example, in a 12-week trial of 74 adults with obesity and diabetes, hypertension, or dyslipidemia, participants randomized to phentermine diffuse-controlled release (30 mg) lost significantly more weight (-8.1 versus -1.7 kg), compared with placebo [104]. Earlier trials of phentermine have demonstrated similar results [105,106].

●Adverse effects and contraindications – Sympathomimetic drugs are contraindicated in patients with coronary heart disease, uncontrolled hypertension, hyperthyroidism, or a history of drug abuse (table 2). All sympathomimetic drugs can increase heart rate and blood pressure and cause insomnia, dry mouth, constipation, and nervousness.

Although no randomized trials of phentermine have examined long-term cardiovascular outcomes, a retrospective analysis of over 13,000 individuals found no increase in cardiovascular events in patients using phentermine for longer than 12 months compared with those using phentermine for less than three months [107].

Phentermine and diethylpropion are Schedule IV drugs, a regulatory classification suggesting potential for abuse; although, the actual observed rate is very low. Benzphetamine and phendimetrazine are Schedule III drugs.

THERAPIES NOT RECOMMENDED — The following therapies are poorly substantiated or with limited data, and some have concern for adverse effects.

●Dietary supplements – Clinicians should caution patients against the use of weight loss dietary supplements and should monitor those who choose to use them. Over-the-counter dietary supplements are widely used by individuals attempting to lose weight, but evidence to support their efficacy and safety is limited. Dietary supplements for weight loss are reviewed in detail elsewhere. (See "High-risk dietary supplements: Patient evaluation and counseling".)

•Safety – Dietary supplements for weight loss can contain stimulants, diuretics, and other prescription drugs that could potentially lead to adverse effects and drug-drug interactions. US Food and Drug Administration laboratory tests have revealed the presence of sibutramine, fenproporex, fluoxetine, bumetanide, furosemide, phenytoin, cetilistat, and phenolphthalein in weight loss products being sold over the counter (table 3) [108]. Two compounded dietary supplements imported from Brazil, Emagrece Sim (also known as the Brazilian diet pill) and Herbathin dietary supplement, have been shown to contain prescription drugs, including amphetamines, benzodiazepines, and fluoxetine. In one report, 18 percent of female Brazilian immigrants were using these drugs while living in the United States; two-thirds reported adverse effects [109].

In addition, a study of two weight loss preparations containing bitter orange (Citrus aurantium), a botanical source of synephrine, showed a non-dose-related increase in heart rate and blood pressure; the cardiovascular effects were postulated to relate to caffeine and other stimulants in the multicomponent formulations [110]. The use of Garcinia cambogia has been associated with hepatic failure [111,112].

Ephedrine is a sympathomimetic amine with a prolonged duration of action, increased peripheral actions, and decreased central actions on adrenergic receptors. Ephedra and ephedra alkaloids (Ma huang) are a group of ephedrine-like molecules found in plants. Ephedrine stimulates weight loss, at least in part, by increasing thermogenesis and by reducing food intake. Because of safety concerns, ephedrine with or without caffeine and the ephedra alkaloids are not approved for treatment of obesity and have been removed from the market [113-115].

•Efficacy – Reviews and meta-analyses of available dietary supplements suggest that most are ineffective or their efficacy is unclear [116]. As examples:

-Green tea [117], Garcinia cambogia (hydroxycitric acid) [118], conjugated linoleic acid, and chitosan were ineffective for weight loss, and their use should be discouraged.

-Efficacy and safety data were unclear for chromium, Gambisan, Hoodia gordonii, and Cynanchum auriculatum [119].

-Guar gum preparations derived from the Indian cluster bean are not effective for weight loss and cause adverse events such as abdominal pain, flatulence, and diarrhea [120].

●Human chorionic gonadotropin – Human chorionic gonadotropin (hCG) should not be used for the treatment of obesity. Several randomized trials have shown that the hCG diet is not more effective than placebo in the treatment of obesity [121,122]. Although hCG injections, pills, or sublingual diet drops have been advertised to aid in weight loss, clinical trials do not support this claim. Among the values claimed for this treatment are loss of 1 to 2 pounds daily, absence of hunger, and maintenance of muscle tone. An integral component of the hCG diet is adherence to a very low-calorie diet (500 kcal/day), which has been recognized to result in short-term weight loss simply from caloric restriction, with no added benefit from hCG. In addition, very low-calorie diets have not been shown to be superior to conventional diets for long-term weight loss. (See "Obesity in adults: Dietary therapy", section on 'Very low-calorie diets'.)

●Calcium – While epidemiologic data suggested that calcium supplementation might be associated with weight loss [123], a meta-analysis of randomized trials evaluating the effect of calcium (through supplementation or dairy food intake) on body weight reported no significant effect of calcium on weight loss [124].

●Other agents – Several drugs marketed for weight loss have been removed from the market after clinical trials revealed increased risks of adverse events, including cancer, adverse cardiovascular events, pulmonary hypertension, hemorrhagic stroke, and psychiatric side effects. These include lorcaserin, sibutramine, phenylpropanolamine, rimonabant, and "fen-phen" (fenfluramine-phentermine) [125-130].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Obesity in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Weight loss treatments (The Basics)")

●Beyond the Basics topics (see "Patient education: Losing weight (Beyond the Basics)" and "Patient education: Weight loss surgery and procedures (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Role of behavioral interventions – All individuals with overweight (body mass index [BMI] ≥25 kg/m²) or obesity (BMI ≥30 kg/m²) should receive counseling on diet, lifestyle, and goals for weight loss. (See 'Role of behavioral interventions' above and "Obesity in adults: Overview of management".)

●Approach to comorbidities – For patients with comorbidities (eg, depression, diabetes), we prefer a holistic approach to chronic disease management by using medications to treat the comorbidity that do not have weight gain as a side effect, when possible (table 1). (See 'Addressing comorbidities' above.)

●Candidates for pharmacotherapy – Candidates for drug therapy include individuals with a BMI ≥30 kg/m², or a BMI of 27 to 29.9 kg/m² with comorbidities, who have not met weight loss goals (weight loss of at least 5 percent of total body weight at three to six months or unable to maintain this weight loss long term) with a comprehensive lifestyle intervention. (See 'Candidates for drug therapy' above.)

●Choice of agent – We consider medication efficacy, contraindications, availability, coverage by insurance, cost, and patient preferences when selecting an antiobesity drug (table 2 and algorithm 1). (See 'Key considerations' above.)

•Incretin-based therapies preferred – For individuals with overweight or obesity in whom pharmacologic therapy is indicated, we suggest tirzepatide or semaglutide rather than other agents (Grade 2C). Indirect comparisons suggest that they may have superior efficacy for weight loss. (See 'Incretin-based therapies preferred' above.)

The selection between tirzepatide and semaglutide depends on patient preferences and comorbidities. Tirzepatide likely results in greater weight loss, but semaglutide has demonstrated reductions in major cardiovascular events in individuals both with and without diabetes. Liraglutide and dulaglutide (for those with diabetes) are acceptable but less efficacious alternatives. However, they also have likely cardiovascular and kidney benefits in the subset of patients with diabetes and with or at high risk of cardiovascular disease (CVD). (See 'Preferred medications' above and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)

•Alternatives to incretin-based therapies – Many individuals cannot access or tolerate glucagon-like peptide 1 receptor agonists, have an inadequate response to them, or prefer an oral medication.

For these patients, we suggest phentermine-topiramate rather than other oral options (Grade 2C). Indirect comparisons suggest that it may have superior efficacy, and its once-daily dosing is convenient. Naltrexone-bupropion, orlistat, and phentermine alone are reasonable alternatives. Phentermine-topiramate and naltrexone-bupropion are contraindicated in those with CVD (table 2 and figure 1). (See 'Alternative agents' above.)

●Monitoring and follow-up – We initially follow up frequently with patients for medication titration and monitoring of weight, other vital signs, and side effects, including hypoglycemia in those with diabetes. (See 'Monitoring' above.)

●Long-term treatment for weight maintenance – If a patient is successful in losing weight with pharmacotherapy, we continue the medication indefinitely to maintain weight loss. Medication discontinuation usually results in weight regain (figure 2).

●Alternative options for patients who do not respond to pharmacotherapy – For patients who do not have an adequate response to pharmacotherapy, bariatric surgery is an option for those who meet surgical criteria. (See 'Monitoring' above and "Obesity in adults: Overview of management", section on 'Bariatric surgery' and "Bariatric surgery for management of obesity: Indications and preoperative preparation", section on 'Indications'.)

●Dietary supplements not recommended – We do not use dietary supplements marketed for weight loss, owing to low-quality evidence of efficacy and concern for potential adverse effects (table 3). (See 'Therapies not recommended' above and "High-risk dietary supplements: Patient evaluation and counseling", section on 'Weight loss supplements'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges George Bray, MD, who contributed to an earlier version of this topic review.