In an adult with obesity (BMI ≥ 30 kg/m² or BMI ≥ 27 kg/m² with hypertension, dyslipidemia, type 2 diabetes, or obstructive sleep apnea) who has not lost ≥5 % body weight after at least three months of intensive lifestyle modification, what are the FDA‑approved pharmacologic options, their dosing regimens, contraindications, and monitoring recommendations?

FDA-Approved Pharmacologic Options for Obesity

For adults with BMI ≥30 kg/m² or BMI ≥27 kg/m² with obesity-related comorbidities who have failed to lose ≥5% body weight after at least 3 months of intensive lifestyle modification, five FDA-approved long-term anti-obesity medications are available: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine/topiramate ER, naltrexone/bupropion ER, and orlistat. 1, 2

Patient Selection Criteria

• Initiate pharmacotherapy for adults with BMI ≥30 kg/m² without additional risk factors, or BMI ≥27 kg/m² with at least one weight-related comorbidity (hypertension, dyslipidemia, type 2 diabetes, or obstructive sleep apnea). 1, 2
• All anti-obesity medications must be prescribed as adjuncts to ongoing lifestyle modification (reduced-calorie diet with 500-1000 kcal/day deficit and ≥150 minutes/week of moderate-intensity physical activity); pharmacotherapy as monotherapy does not meet FDA approval criteria. 1, 2
• For Asian populations, consider lower BMI thresholds: pharmacotherapy at BMI ≥27 kg/m² or ≥25 kg/m² with complications, as Asian individuals develop obesity-related complications at lower BMI levels. 1, 2

FDA-Approved Medications: Dosing & Expected Efficacy

First-Line GLP-1 Receptor Agonists

Semaglutide 2.4 mg (Wegovy)

• Dosing: Start 0.25 mg subcutaneously once weekly; titrate monthly (0.5 mg → 1.0 mg → 1.7 mg → 2.4 mg maintenance dose). 1, 2
• Expected weight loss: 15-20% of initial body weight over 52-72 weeks. 1, 2
• Contraindications: Personal or family history of medullary thyroid carcinoma, multiple endocrine neoplasia syndrome type 2, pregnancy, active gallbladder disease. 1
• Common side effects: Nausea, vomiting, diarrhea, constipation, abdominal pain (typically resolve with slow titration). 1, 2

Liraglutide 3.0 mg (Saxenda)

• Dosing: Start 0.6 mg subcutaneously daily; increase by 0.6 mg weekly to 3.0 mg maintenance dose. 1, 2
• Expected weight loss: 8-10% of initial body weight over 56 weeks. 1
• Contraindications: Same as semaglutide (medullary thyroid carcinoma history, MEN 2, pregnancy). 1
• Preferred for: Patients with type 2 diabetes due to dual metabolic benefits. 1, 2
• Common side effects: Nausea, diarrhea, constipation, hypoglycemia (when combined with insulin or sulfonylureas). 1

Combination Agents

Phentermine/Topiramate ER (Qsymia)

• Dosing: Start 3.75 mg/23 mg daily for 14 days; increase to 7.5 mg/46 mg daily; if inadequate response after 12 weeks, escalate to 11.25 mg/69 mg for 14 days, then 15 mg/92 mg daily. 1
• Expected weight loss: 9-10% of initial body weight over 56 weeks. 1
• Contraindications: Pregnancy (teratogenic—requires negative pregnancy test before initiation and monthly thereafter), glaucoma, hyperthyroidism, cardiovascular disease (uncontrolled hypertension, coronary artery disease, arrhythmias), monoamine oxidase inhibitor use within 14 days. 1, 2
• Common side effects: Paresthesias, dry mouth, constipation, insomnia, dysgeusia, cognitive impairment. 1
• Critical precaution: Avoid in patients with cardiovascular disease; choose GLP-1 agonists, naltrexone/bupropion, or orlistat instead. 2

Naltrexone/Bupropion ER (Contrave)

• Dosing: Start 8 mg/90 mg daily; titrate weekly (week 2: twice daily; week 3: morning 2 tablets + evening 1 tablet; week 4: 2 tablets twice daily for 16 mg/360 mg total daily). 1
• Expected weight loss: 5-6% of initial body weight over 56 weeks. 1
• Contraindications: Uncontrolled hypertension, seizure disorders, eating disorders (bulimia, anorexia nervosa), chronic opioid use, abrupt discontinuation of alcohol or benzodiazepines, monoamine oxidase inhibitor use within 14 days, pregnancy. 1
• Common side effects: Nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth. 1

Lipase Inhibitor

Orlistat (Xenical 120 mg; Alli 60 mg OTC)

• Dosing: 120 mg three times daily with each fat-containing meal (or up to 1 hour after); skip dose if meal is fat-free. 1, 2
• Expected weight loss: 3-4% (approximately 2.9 kg) of initial body weight over 12 months. 1, 2
• Contraindications: Chronic malabsorption syndrome, cholestasis, pregnancy. 1
• Common side effects: Fecal urgency, oily spotting, flatulence with discharge, abdominal cramping (reduced by limiting dietary fat to <30% of calories). 1, 2
• Monitoring: Risk of fat-soluble vitamin deficiency (A, D, E, K); recommend daily multivitamin taken ≥2 hours before or after orlistat. Monitor for potential malabsorption of cyclosporine, levothyroxine, anticonvulsants. 1
• Rare serious risks: Severe liver injury (monitor liver enzymes if symptoms develop), cholelithiasis, nephrolithiasis (calcium oxalate stones). 1

Short-Term Sympathomimetic (Not for Chronic Use)

Phentermine (Adipex-P)

• Dosing: 15-37.5 mg once daily, taken approximately 2 hours after breakfast. 1, 2
• Duration: FDA-approved for short-term use only (≤12 weeks); not recommended for chronic weight management. 1, 2
• Expected weight loss: 6.1% over 6 months (not sustained long-term). 1
• Contraindications: Cardiovascular disease, uncontrolled hypertension, hyperthyroidism, glaucoma, agitated states, history of drug abuse, monoamine oxidase inhibitor use within 14 days. 1
• Common side effects: Dry mouth, insomnia, dizziness, irritability, increased heart rate and blood pressure. 1

Medication Selection Algorithm

Step 1: Assess for type 2 diabetes

• If present: Prioritize GLP-1 receptor agonists (semaglutide 2.4 mg or liraglutide 3.0 mg) for dual metabolic benefits (glycemic control + weight loss). 1, 2

Step 2: Assess for cardiovascular disease

• If present: Avoid sympathomimetic agents (phentermine, phentermine/topiramate); choose GLP-1 agonists, naltrexone/bupropion, or orlistat. 2

Step 3: Assess for seizure disorder or eating disorder

• If present: Avoid naltrexone/bupropion and phentermine/topiramate; choose GLP-1 agonists or orlistat. 1

Step 4: Assess pregnancy plans

• If pregnancy possible: Avoid phentermine/topiramate (teratogenic); require reliable contraception or choose alternative agents. All anti-obesity medications are contraindicated in pregnancy. 1

Step 5: Consider patient preference and tolerability

• Injectable preferred + maximal efficacy needed: Semaglutide 2.4 mg (15-20% weight loss). 2
• Injectable acceptable + type 2 diabetes present: Liraglutide 3.0 mg (8-10% weight loss). 2
• Oral preferred + no cardiovascular disease: Phentermine/topiramate ER (9-10% weight loss). 1
• Oral preferred + cardiovascular disease present: Naltrexone/bupropion ER (5-6% weight loss). 1
• Cost-sensitive or gastrointestinal side effects tolerable: Orlistat (3-4% weight loss, available OTC at lower dose). 1, 2

Monitoring Recommendations

Initial 3 months:

• Assess efficacy and safety monthly during the first 3 months. 1, 2
• Measure body weight at each visit; calculate percentage weight loss from baseline. 1
• Monitor blood pressure, heart rate (especially with sympathomimetics), and symptoms of adverse effects. 1

Continuation decision at 3 months:

• Continue medication if patient achieves ≥5% weight loss from baseline at 3 months on the maximally tolerated dose; early responders (≥5% loss at 3 months) are likely to achieve sustained long-term weight loss. 1, 2
• Discontinue medication if weight loss is <5% after 3 months at the therapeutic dose, as this predicts poor long-term response; consider switching to an alternative medication or escalating to bariatric surgery referral. 1, 2

Ongoing monitoring (after 3 months):

• Assess at least every 3 months thereafter for weight trajectory, medication adherence, adverse effects, and obesity-related comorbidities. 1, 2
• Monitor improvements in secondary metabolic parameters: blood pressure, fasting glucose or HbA1c, lipid panel, liver enzymes. 2
• For orlistat: monitor for signs of fat-soluble vitamin deficiency (night blindness, bone pain, easy bruising, bleeding). 1
• For GLP-1 agonists: monitor for pancreatitis symptoms (severe abdominal pain), gallbladder disease, and hypoglycemia (if on concurrent insulin or sulfonylureas). 1

Duration of Therapy

• Anti-obesity medications are intended for long-term, potentially lifelong use to maintain weight loss; weight regain is common when medication is discontinued. 1, 2
• Extended treatment is necessary to support weight maintenance and provide sustained health benefits for obesity-related complications. 1
• Discontinue only if: (1) inadequate response (<5% weight loss at 3 months), (2) significant safety or tolerability issues arise, or (3) patient achieves weight-loss goals and prefers to attempt maintenance with lifestyle modification alone (though relapse risk is high). 1

Concomitant Medication Management

• Review the patient's medication list for weight-promoting agents (antipsychotics, tricyclic antidepressants, gabapentin, insulin, sulfonylureas, thiazolidinediones, corticosteroids) and consider alternatives when feasible. 1, 2
• For patients with type 2 diabetes, prioritize glucose-lowering medications with weight-neutral or weight-loss effects (metformin, SGLT2 inhibitors, GLP-1 agonists); minimize or avoid insulin secretagogues, thiazolidinediones, and insulin when possible. 1, 2
• If weight-promoting medications cannot be discontinued, adding metformin (≈1000 mg daily) or topiramate (≈100 mg daily) may help mitigate iatrogenic weight gain. 2

Critical Pitfalls to Avoid

• Do not prescribe anti-obesity medication as monotherapy; it must be combined with ongoing lifestyle modification (reduced-calorie diet and ≥150 minutes/week physical activity) to meet FDA approval criteria and maximize efficacy. 1, 2
• Do not continue ineffective treatment beyond 12 weeks at maintenance dose if <5% weight loss is achieved; this represents treatment failure and warrants switching to an alternative medication or escalating care. 1, 2
• Do not use phentermine or phentermine/topiramate in patients with cardiovascular disease (uncontrolled hypertension, coronary artery disease, arrhythmias); choose GLP-1 agonists, naltrexone/bupropion, or orlistat instead. 1, 2
• Do not prescribe phentermine/topiramate without confirming negative pregnancy test and reliable contraception in women of reproductive potential; this medication is highly teratogenic. 1
• Do not overlook bariatric surgery referral for patients with BMI ≥35 kg/m² with comorbidities or BMI ≥40 kg/m² who fail pharmacotherapy; surgery achieves greater weight loss (25-30%) and reduces cardiovascular morbidity and mortality. 1, 2