What FDA‑approved pharmacologic agents are recommended for an adult with a body‑mass index ≥30 kg/m² (or ≥27 kg/m² with a weight‑related comorbidity) after lifestyle modification, including indications, dosing, contraindications, and monitoring requirements?

FDA-Approved Pharmacologic Agents for Obesity Management

Patient Eligibility Criteria

Adults with BMI ≥30 kg/m² qualify for anti-obesity pharmacotherapy without additional requirements, while those with BMI ≥27 kg/m² require at least one weight-related comorbidity such as hypertension, dyslipidemia, type 2 diabetes, or obstructive sleep apnea. 1, 2 All pharmacologic agents must be combined with a reduced-calorie diet (approximately 500-kcal daily deficit) and minimum 150 minutes per week of moderate-intensity physical activity—monotherapy without lifestyle modification fails to meet FDA approval criteria and produces suboptimal outcomes. 1

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First-Line Pharmacologic Options

GLP-1 Receptor Agonists (Preferred)

Semaglutide 2.4 mg weekly (Wegovy) should be prioritized as first-line therapy for most patients, achieving 14.9% mean weight loss at 68 weeks with 64.9% of patients reaching ≥10% weight reduction. 1, 2 For patients with established cardiovascular disease, semaglutide provides an additional 20% reduction in cardiovascular death, nonfatal MI, or stroke (HR 0.80), making it the definitive choice in this population. 1, 2

Tirzepatide 15 mg weekly (Zepbound/Mounjaro) produces superior weight loss of 20.9% at 72 weeks—approximately 6% greater than semaglutide—and should be selected when maximum weight reduction is the primary goal. 1, 2 Tirzepatide demonstrates broader cardiometabolic benefits including greater waist circumference reduction, superior triglyceride lowering, and better fasting glucose control compared to semaglutide. 2

Liraglutide 3.0 mg daily (Saxenda) achieves 5.2–6.1% weight loss and may be considered when weekly injections are refused or not tolerated, though its efficacy is substantially lower than semaglutide or tirzepatide. 1, 3

Dosing & Titration

• Semaglutide: Start 0.25 mg weekly × 4 weeks → 0.5 mg × 4 weeks → 1.0 mg × 4 weeks → 1.7 mg × 4 weeks → 2.4 mg maintenance (reached at week 17). 1, 2
• Tirzepatide: Start 5 mg weekly × 4 weeks → 10 mg × 4 weeks → 15 mg maintenance. 1, 2
• Liraglutide: Start 0.6 mg daily × 1 week → 1.2 mg × 1 week → 1.8 mg × 1 week → 2.4 mg × 1 week → 3.0 mg maintenance. 3

Contraindications

• Absolute: Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN2). 1, 2
• Relative cautions: History of pancreatitis (causality not definitively established), symptomatic gallbladder disease (38% increased risk of cholelithiasis/cholecystitis with semaglutide). 1, 2

Monitoring Requirements

• Weeks 0–16 (titration phase): Assess every 4 weeks for gastrointestinal tolerance, weight loss progress, blood pressure, and signs of pancreatitis or gallbladder disease. 1, 2
• After week 16: Monitor at least every 3 months for weight stability, cardiovascular risk factors, medication adherence, and adverse effects. 1, 2
• Treatment response evaluation: Discontinue if <5% weight loss after 12–16 weeks at therapeutic dose, as early non-responders are unlikely to benefit from continued therapy. 1, 2

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Oral Combination Agents

Phentermine/topiramate ER (Qsymia) produces 8.45% weight loss and is the most effective oral option, but should be avoided in patients with cardiovascular disease. 1, 4, 5 Start 3.75 mg/23 mg daily × 14 days → 7.5 mg/46 mg daily; if <3% weight loss after 12 weeks, increase to 11.25 mg/69 mg × 14 days → 15 mg/92 mg daily. 5 Discontinue if <5% weight loss after 12 weeks at maximum dose. 5

• Contraindications: Pregnancy (teratogenic risk from topiramate), glaucoma, hyperthyroidism, cardiovascular disease, MAO inhibitor use within 14 days. 5
• Monitoring: Blood pressure and heart rate at each visit; serum creatinine and potassium periodically (topiramate can cause metabolic acidosis and kidney stones). 5

Naltrexone SR/bupropion SR (Contrave) achieves 3.01% weight loss and may be particularly appropriate for patients with comorbid depression. 1, 6, 5 Start 8 mg/90 mg daily × 1 week → 8 mg/90 mg twice daily × 1 week → 16 mg/180 mg AM + 8 mg/90 mg PM × 1 week → 16 mg/180 mg twice daily (maintenance). 6, 5

• Contraindications: Uncontrolled hypertension, seizure disorders, eating disorders, opioid use, MAO inhibitor use within 14 days, pregnancy/breastfeeding. 6, 5
• Monitoring: Blood pressure and heart rate at baseline and regularly during treatment; neuropsychiatric symptoms (bupropion carries black-box warning for suicidality). 6, 5

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Lipase Inhibitor

Orlistat 120 mg three times daily (Xenical) reduces fat absorption and produces modest weight loss of approximately 2.9 kg at 12 months, but gastrointestinal adverse effects (abdominal pain, diarrhea, fecal urgency) limit tolerability. 1 Take with each fat-containing meal (up to 3 times daily); skip dose if meal is fat-free. 1

• Monitoring: Fat-soluble vitamin levels (A, D, E, K) annually; supplement with multivitamin taken 2 hours before or after orlistat. 1
• Contraindications: Chronic malabsorption syndrome, cholestasis. 1

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Short-Term Sympathomimetic (Not Recommended for Chronic Management)

Phentermine monotherapy is FDA-approved only for short-term use (≤12 weeks) and should not be considered for chronic weight management. 1 Dose 15–30 mg daily, taken approximately 2 hours after breakfast. 1 Avoid in patients with cardiovascular disease, uncontrolled hypertension, or hyperthyroidism. 1, 5

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Clinical Decision Algorithm

1. Screen for absolute contraindications (medullary thyroid cancer/MEN2 for GLP-1 RAs; pregnancy for phentermine/topiramate; seizure disorder for naltrexone/bupropion). 1, 2, 6

2. Assess cardiovascular disease status:

   • Established CVD present: Semaglutide 2.4 mg weekly (proven 20% MACE reduction). 1, 2
   • No CVD, maximum weight loss needed: Tirzepatide 15 mg weekly (20.9% weight loss). 1, 2

3. If GLP-1 RAs contraindicated or unavailable:

   • No CVD: Phentermine/topiramate ER (8.45% weight loss). 1, 5
   • CVD present: Naltrexone/bupropion SR (3.01% weight loss) or orlistat (avoid phentermine/topiramate). 1, 5

4. Evaluate response at 12–16 weeks:

   • ≥5% weight loss: Continue therapy long-term with quarterly monitoring. 1, 2
   • <5% weight loss: Discontinue and switch to alternative agent or consider metabolic surgery. 1, 2

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Concomitant Medication Management

Review all current medications to identify weight-promoting agents (antipsychotics, tricyclic antidepressants, gabapentin, insulin, corticosteroids) and consider alternatives when feasible. 1 For patients with diabetes, prioritize glucose-lowering medications with weight loss or weight-neutral effects (metformin, SGLT2 inhibitors, GLP-1 RAs) and minimize insulin secretagogues, thiazolidinediones, and insulin. 1

When initiating GLP-1 RAs in patients on insulin or sulfonylureas, reduce basal insulin by 20% and discontinue or reduce sulfonylurea dose by 50% to prevent hypoglycemia. 1, 2

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Metabolic Surgery Consideration

Metabolic surgery should be offered to patients with BMI ≥40 kg/m² (≥37.5 kg/m² in Asian Americans) or BMI 35–39.9 kg/m² (32.5–37.4 kg/m² in Asian Americans) who fail to achieve durable weight loss with pharmacotherapy. 1 Surgery may be considered for BMI 30–34.9 kg/m² (27.5–32.4 kg/m² in Asian Americans) if medical management fails. 1

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Critical Pitfalls to Avoid

• Do not prescribe anti-obesity medications as monotherapy—they must be combined with lifestyle modification throughout treatment to meet FDA approval criteria and maximize efficacy. 1
• Do not continue ineffective treatment beyond 12 weeks at maintenance dose if <5% weight loss is achieved; switch to an alternative medication or expedite surgical referral. 1, 2
• Do not combine anti-obesity medications without clinical trial data supporting the safety and efficacy of the combination—no evidence supports combination therapy. 7
• Do not delay bariatric surgery referral in patients with BMI >60 kg/m², as medication alone will not achieve sufficient weight loss to meaningfully reduce morbidity and mortality. 1