What are the recommended medications for weight loss?

FDA-Approved Weight Loss Medications

For most patients seeking weight loss medication, semaglutide 2.4 mg weekly (Wegovy) or tirzepatide should be the first-line choice due to superior efficacy (15-21% weight loss) and cardiovascular benefits. 1, 2

Patient Selection Criteria

Pharmacotherapy is indicated for patients with: 3, 1, 2

• BMI ≥30 kg/m² OR
• BMI ≥27 kg/m² with weight-related comorbidities (type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea)

All medications must be combined with lifestyle interventions including reduced-calorie diet, increased physical activity, and behavioral counseling—never use medications alone. 3, 2

First-Line Medication Options

GLP-1 Receptor Agonists (Preferred)

Semaglutide 2.4 mg (Wegovy):

• Most effective option with up to 21% mean weight loss at 72 weeks 2
• Weekly subcutaneous injection 2
• Provides cardiovascular benefits beyond weight loss 1, 2
• Common side effects: nausea, diarrhea, constipation, vomiting, abdominal pain 3

Liraglutide 3.0 mg (Saxenda):

• 5.4% mean weight loss at 56 weeks 3, 1
• Daily subcutaneous injection starting at 0.6 mg, escalating by 0.6 mg weekly to 3.0 mg 3, 1
• Alternative when semaglutide unavailable 1

Alternative First-Line Options

Phentermine/Topiramate ER (Qsymia):

• 6.6% mean weight loss at 1 year 3, 1
• Dose escalation: start 3.75/23 mg daily, increase gradually to maximum 15/92 mg daily 3
• Contraindicated in cardiovascular disease, pregnancy, glaucoma, hyperthyroidism 3, 1, 4
• Requires monthly pregnancy testing in women of reproductive age 1
• Schedule IV controlled substance 3

Naltrexone SR/Bupropion SR (Contrave):

• 4.8% mean weight loss at 56 weeks 3
• Start 8/90 mg daily, escalate to 16/180 mg twice daily 3
• Moderate efficacy, useful when GLP-1 agonists contraindicated 2

Orlistat (Xenical 120 mg/Alli 60 mg OTC):

• 3.1% mean weight loss at 1 year 3, 1
• Blocks ~30% of dietary fat absorption 3, 1, 2
• 120 mg three times daily with meals containing fat 3
• Requires daily multivitamin supplementation (fat-soluble vitamins A, D, E, K taken 2 hours before or after orlistat) 3, 1
• Budget-friendly option, safest for cardiovascular disease and renal impairment 1, 5
• Side effects: oily spotting, fecal urgency, fatty stools, fecal incontinence 3

Short-Term Option (Off-Label for Long-Term)

Phentermine monotherapy (Adipex):

• FDA-approved only for short-term use (few weeks), but commonly prescribed off-label 3, 4
• 5.1% weight loss at 28 weeks; 46% of patients achieve ≥5% weight loss 1
• 15-30 mg daily, taken 2 hours after breakfast 4
• Contraindicated in cardiovascular disease, uncontrolled hypertension, hyperthyroidism, glaucoma 4
• Monitor blood pressure and heart rate monthly 1
• Schedule IV controlled substance with abuse potential 3, 4
• Avoid late evening dosing due to insomnia risk 4

Clinical Decision Algorithm

Step 1: Assess for cardiovascular disease

• If CVD present: Use orlistat or liraglutide; avoid phentermine and phentermine/topiramate 3, 1
• If no CVD: Proceed to Step 2

Step 2: Consider efficacy needs and patient preference

• For maximum weight loss: Semaglutide 2.4 mg or tirzepatide 1, 2
• For oral medication preference: Phentermine/topiramate or naltrexone/bupropion 1, 2
• For budget constraints or insurance limitations: Orlistat (available OTC as Alli 60 mg) 1, 2
• For patients with constipation: Orlistat may provide dual benefit 1

Step 3: Special populations

• Type 2 diabetes: Prioritize GLP-1 agonists (semaglutide, liraglutide) for glycemic control plus weight loss 3
• Renal impairment (eGFR 15-29): Maximum phentermine dose 15 mg daily; avoid if eGFR <15 4
• Women of reproductive age: Ensure reliable contraception with phentermine/topiramate; monthly pregnancy testing required 1

Monitoring and Efficacy Assessment

• Assess monthly for first 3 months, then quarterly thereafter 3, 1, 2
• Discontinue or switch medication if <5% weight loss after 3 months at therapeutic dose 3, 1, 2
• Continue medication beyond reaching weight loss goals to maintain benefits—obesity is a chronic disease requiring indefinite treatment 1, 2
• Sudden discontinuation often results in weight regain and worsening cardiometabolic risk factors 2

Critical Pitfalls to Avoid

• Never combine phentermine with other weight loss medications—safety and efficacy of combination therapy not established 3, 4
• Do not exceed recommended phentermine doses when tolerance develops—discontinue instead 4
• Review concomitant medications that promote weight gain (antipsychotics, some antidepressants, glucocorticoids, β-blockers) and consider alternatives 1, 2
• Avoid β-blockers as antihypertensives in obesity—they promote weight gain 1
• Do not use medications without concurrent lifestyle modifications—diet and exercise are essential 3, 2
• Patients on insulin or oral hypoglycemics may require dose reduction with weight loss 4

Access Considerations

Medicare currently excludes coverage of FDA-approved anti-obesity medications for obesity alone, creating significant access barriers. 2 Global shortages of GLP-1 receptor agonists may affect availability. 2 In these situations, phentermine/topiramate, naltrexone/bupropion, or orlistat serve as accessible alternatives. 1, 2