What FDA‑approved weight‑loss medications (orlistat, phentermine/topiramate (Qsymia), naltrexone/bupropion (Contrave), liraglutide (Saxenda), semaglutide (Wegovy)) are appropriate for an adult with a body‑mass index ≥30 kg/m² (or ≥27 kg/m² with an obesity‑related comorbidity) who has failed at least three months of diet, exercise and behavioral therapy, and what are their dosing regimens, contraindications, and monitoring requirements?

FDA-Approved Weight Loss Medications for Adults with Obesity

For adults with BMI ≥30 kg/m² (or ≥27 kg/m² with obesity-related comorbidities) who have failed lifestyle modification, initiate pharmacotherapy with semaglutide 2.4 mg weekly or tirzepatide 15 mg weekly as first-line agents, combined with mandatory lifestyle interventions including a 500-kcal deficit diet and ≥150 minutes weekly of physical activity. 1, 2

Patient Eligibility Criteria

• BMI thresholds: Pharmacotherapy is indicated for BMI ≥30 kg/m² without additional risk factors, or BMI ≥27 kg/m² with at least one weight-related comorbidity (hypertension, type 2 diabetes, dyslipidemia, obstructive sleep apnea). 1
• Prior lifestyle intervention: Patients must have attempted at least 3 months of diet, exercise, and behavioral therapy without achieving adequate weight loss or weight maintenance. 1
• Mandatory concurrent therapy: All FDA-approved weight loss medications require combination with reduced-calorie diet (500-kcal deficit) and minimum 150 minutes weekly of moderate-intensity physical activity—pharmacotherapy alone does not meet FDA approval criteria. 1, 2

First-Line Medication Selection Algorithm

Preferred First-Line: GLP-1 Receptor Agonists

Semaglutide (Wegovy) 2.4 mg weekly is the preferred choice for patients with established cardiovascular disease or high cardiovascular risk, achieving 14.9-17.4% weight loss at 68 weeks and reducing cardiovascular events by 20% (HR 0.80). 2, 3, 4

• Dosing regimen: Start 0.25 mg subcutaneously once weekly for 4 weeks, then escalate to 0.5 mg weekly for 4 weeks, then 1.0 mg weekly for 4 weeks, then 1.7 mg weekly for 4 weeks, then maintenance dose of 2.4 mg weekly. 1
• Expected weight loss: 11.4% greater than placebo (14.9-17.4% total weight loss) over 68 weeks. 4, 2
• Cardiovascular benefit: 20% reduction in cardiovascular death, nonfatal MI, or nonfatal stroke in patients with obesity and established CVD. 3, 2
• Common adverse effects: Nausea (28-44%), diarrhea (21-30%), vomiting (7-25%), constipation (11-24%). 3, 4
• Contraindications: Pregnancy, personal or family history of medullary thyroid carcinoma, multiple endocrine neoplasia syndrome type 2. 1

Liraglutide (Saxenda) 3.0 mg daily is an alternative GLP-1 agonist, particularly beneficial for patients with type 2 diabetes, achieving 5.4% weight loss at 56 weeks. 1, 5

• Dosing regimen: Start 0.6 mg subcutaneously once daily, escalate by 0.6 mg weekly up to maintenance dose of 3.0 mg daily. 1
• Expected weight loss: 5.4% greater than placebo (4.7% in meta-analysis) at 56 weeks. 1, 5, 4
• Common adverse effects: Nausea, hypoglycemia (in diabetics), diarrhea, constipation, vomiting, headache, dizziness, abdominal pain. 1
• Contraindications: Pregnancy, personal or family history of medullary thyroid carcinoma, multiple endocrine neoplasia syndrome type 2. 1

Alternative First-Line Options

Phentermine/Topiramate ER (Qsymia) achieves the highest weight loss among non-GLP-1 agents (6.6-8.0% greater than placebo) but is contraindicated in cardiovascular disease. 1, 5, 4

• Dosing regimen: Start 3.75 mg/23 mg daily for 14 days, then escalate to 7.5 mg/46 mg daily. If inadequate response after 12 weeks, increase to 11.25 mg/69 mg daily for 14 days, then 15 mg/92 mg daily (maximum dose). 1
• Expected weight loss: 6.6-8.0% greater than placebo at 1 year. 1, 5, 4
• Common adverse effects: Paresthesia, dizziness, dysgeusia, insomnia, constipation, dry mouth. 1
• Contraindications: Pregnancy, glaucoma, hyperthyroidism, cardiovascular disease, during or within 14 days of MAOIs, other sympathomimetic amines. 1, 6
• Schedule IV controlled substance. 1

Naltrexone SR/Bupropion SR (Contrave) is appropriate for patients without seizure history or uncontrolled hypertension, achieving 4.0-4.8% weight loss. 1, 5, 4

• Dosing regimen: Start 8 mg/90 mg once daily in the morning. Week 2: increase to 8 mg/90 mg twice daily. Week 3: increase to 16 mg/180 mg in morning and 8 mg/90 mg in evening. Week 4 onward: maintenance dose of 16 mg/180 mg twice daily. 1
• Expected weight loss: 4.0-4.8% greater than placebo at 56 weeks. 1, 5, 4
• Common adverse effects: Nausea, constipation, dizziness, insomnia, dry mouth, diarrhea, vomiting, headache, increased lipase. 1
• Contraindications: Pregnancy, uncontrolled hypertension, history of seizures or conditions increasing seizure risk, bulimia or anorexia, use of opioid agonists or partial agonists, during or within 14 days of MAOIs. 1

Orlistat (Xenical) 120 mg is the safest option for patients with cardiovascular disease but has the lowest efficacy (2.9-3.1% weight loss) and significant gastrointestinal side effects. 1, 5, 4

• Dosing regimen: 120 mg three times daily with each main meal containing fat (during or up to 1 hour after the meal). 1
• Expected weight loss: 2.9-3.1% greater than placebo at 1 year. 1, 5, 4
• Common adverse effects: Oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, increased defecation, fecal incontinence (>25% of patients). 1, 4
• Contraindications: Pregnancy, chronic malabsorption syndrome, cholestasis; should not be taken with cyclosporine, levothyroxine, warfarin, or antiepileptic drugs. 1

Comorbidity-Specific Medication Selection

Patients with Cardiovascular Disease

Avoid sympathomimetic agents (phentermine, phentermine/topiramate ER) entirely in patients with established CVD. 1, 2

• Preferred options: Semaglutide 2.4 mg (proven cardiovascular benefit), liraglutide 3.0 mg, naltrexone/bupropion, or orlistat. 1, 2, 3

Patients with Type 2 Diabetes

Prioritize GLP-1 receptor agonists (semaglutide 2.4 mg, liraglutide 3.0 mg, or tirzepatide) due to dual metabolic benefits—weight loss plus HbA1c reduction. 1, 2

• Continue metformin as first-line agent for type 2 diabetes alongside GLP-1 therapy. 1
• No dosage adjustments required for semaglutide or liraglutide in patients with eGFR ≥15 mL/min/1.73m². 1

Patients with Uncontrolled Hypertension or Seizure History

Avoid naltrexone/bupropion in patients with uncontrolled hypertension or history of seizures. 1

• Alternative options: Semaglutide, liraglutide, or orlistat. 1

Patients with Glaucoma or Hyperthyroidism

Avoid phentermine and phentermine/topiramate in patients with glaucoma or hyperthyroidism. 1, 6

Monitoring Requirements

Initial Monitoring (First 3 Months)

Assess efficacy and safety monthly for the first 3 months, evaluating weight loss, tolerability, blood pressure, heart rate, and obesity-related complications. 1, 2

• Measure weight at each visit to track progress toward 5% weight loss threshold. 1
• Monitor blood pressure and heart rate at every visit, especially with sympathomimetic agents. 1, 6
• Screen for adverse effects specific to each medication (gastrointestinal symptoms with GLP-1 agonists and orlistat, neuropsychiatric symptoms with phentermine/topiramate and naltrexone/bupropion). 1, 4

Ongoing Monitoring (After 3 Months)

Continue assessment at least every 3 months after the initial period, monitoring weight, blood pressure, lipids, glucose, and liver enzymes. 1, 2

• Evaluate improvements in obesity-related comorbidities (hypertension, dyslipidemia, type 2 diabetes, sleep apnea). 1, 2
• Monitor for rare but serious adverse effects: pancreatitis, gallbladder disease, acute kidney injury (GLP-1 agonists); metabolic acidosis (phentermine/topiramate); hepatotoxicity (naltrexone/bupropion). 1, 3

Discontinuation Criteria

Discontinue medication if weight loss is <5% of initial body weight after 12 weeks at the maximum tolerated dose, as this predicts poor long-term response. 1, 2

• Consider switching to an alternative medication or escalating to bariatric surgery referral. 1, 2
• Weight regain is common when medication is withdrawn; extended treatment is typically required for sustained benefit. 1, 5

Critical Pitfalls to Avoid

• Never prescribe weight loss medications as monotherapy—they must be combined with lifestyle modification (500-kcal deficit diet and ≥150 minutes weekly physical activity) throughout treatment to meet FDA approval criteria and maximize efficacy. 1, 2
• Do not continue ineffective treatment beyond 12 weeks—if <5% weight loss is achieved at the maximum tolerated dose, discontinue and switch to an alternative medication or refer for bariatric surgery. 1, 2
• Avoid sympathomimetic agents (phentermine, phentermine/topiramate) in patients with cardiovascular disease—use GLP-1 agonists, naltrexone/bupropion, or orlistat instead. 1, 2
• Screen for pregnancy before initiating any weight loss medication—all FDA-approved agents are contraindicated in pregnancy. 1, 6
• Review concomitant medications for weight-promoting agents (antipsychotics, tricyclic antidepressants, gabapentin, insulin, corticosteroids) and consider alternatives when feasible. 2
• Do not use phentermine for long-term management—it is FDA-approved only for short-term use (≤12 weeks) and is not a Schedule IV controlled substance appropriate for chronic weight management. 1, 2, 6

Expected Weight Loss Outcomes by Medication

• Semaglutide 2.4 mg: 11.4-17.4% total weight loss (14.9% average) at 68 weeks. 2, 3, 4
• Phentermine/Topiramate ER: 6.6-8.0% greater than placebo at 1 year. 1, 5, 4
• Liraglutide 3.0 mg: 5.4% greater than placebo at 56 weeks. 1, 5, 4
• Naltrexone/Bupropion: 4.0-4.8% greater than placebo at 56 weeks. 1, 5, 4
• Orlistat: 2.9-3.1% greater than placebo at 1 year. 1, 5, 4

Long-Term Management Considerations

Obesity is a chronic, relapsing disease requiring long-term pharmacotherapy for sustained weight loss and prevention of weight regain. 1, 5, 7

• All FDA-approved medications except phentermine are approved for long-term use. 1, 7
• Weight regain is common when medication is discontinued; lifelong management is typically required. 1, 2, 5
• Behavioral interventions should continue alongside pharmacotherapy to support adherence to healthful lifestyle and improve quality of life. 1