What medications are available for weight loss?

Medications for Weight Loss

For weight loss, start with semaglutide 2.4 mg weekly or tirzepatide as first-line pharmacotherapy, as these GLP-1 receptor agonists achieve the greatest weight reduction (15-21%) with proven cardiovascular benefits. 1, 2

Patient Selection for Pharmacotherapy

Medications are indicated for patients meeting these criteria: 1

• BMI ≥30 kg/m² (obesity), OR
• BMI ≥27 kg/m² with weight-related comorbidities (type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea)
• Failed to achieve weight loss goals through diet and exercise alone

Medication Hierarchy by Efficacy

The treatment hierarchy based on weight loss magnitude: 2

First-Line: GLP-1/GIP Agonists (Most Effective)

• Tirzepatide (dual GIP/GLP-1 agonist): 21% weight loss at 72 weeks—the most effective FDA-approved option with additional glycemic control and cardiovascular risk reduction 1, 2
• Semaglutide 2.4 mg weekly: 15-17% weight loss at 1 year with proven cardiovascular event reduction in patients with obesity and preexisting cardiovascular disease 1, 2, 3
• Liraglutide 3.0 mg daily (Saxenda): 8-10% weight loss, requires daily subcutaneous injection with dose escalation, proven cardiovascular safety 1, 2

Second-Line: Combination Medications

• Phentermine-topiramate extended release: Clinically meaningful weight loss, approved for BMI ≥30 kg/m² or ≥27 kg/m² with comorbidities 2
• Naltrexone-bupropion: 4.8% weight loss at 56 weeks 4, 2

Third-Line: Lipase Inhibitor

• Orlistat (Xenical 120 mg/Alli 60 mg OTC): 2.9 kg weight loss at 12 months, reduces fat absorption, requires fat-soluble vitamin supplementation, best for patients with constipation or limited financial resources 4, 1, 2

Short-Term Use Only

• Phentermine: 3.6-3.75 kg weight loss, FDA-labeled for short-term usage only, avoid in coronary artery disease, uncontrolled hypertension, glaucoma, and substance use disorder history 4, 2
• Diethylpropion: 3.0 kg weight loss of borderline statistical significance 4

Clinical Decision Algorithm

Step 1: Assess patient characteristics 1

• Presence of type 2 diabetes: Choose GLP-1 agonists or tirzepatide for dual glycemic and weight benefits
• Cardiovascular disease history: Choose semaglutide 2.4 mg for proven CV event reduction
• Constipation: Consider orlistat
• Financial constraints: Consider orlistat (available OTC at lower dose)

Step 2: Initiate medication with lifestyle modification 1, 5

• All medications require combination with reduced-calorie diet and physical activity (150-300 minutes moderate-intensity exercise weekly)
• Dose escalation protocols minimize GI side effects with GLP-1 agonists

Step 3: Monitor response 1

• Assess monthly for first 3 months, then quarterly
• Discontinue or change medication if <5% weight loss after 3 months at therapeutic dose

Step 4: Long-term management 1, 2

• Continue medication indefinitely beyond reaching weight loss goals—obesity is a chronic disease requiring ongoing treatment
• Sudden discontinuation results in weight regain and worsening cardiometabolic risk factors

Critical Contraindications and Safety Monitoring

GLP-1 agonists contraindications: 1

• Pregnancy (absolute contraindication)
• Personal or family history of medullary thyroid carcinoma
• Multiple endocrine neoplasia syndrome type 2

Common pitfalls to avoid: 4, 1

• GI side effects (nausea, vomiting, diarrhea) usually improve with gradual dose escalation—do not discontinue prematurely
• Monitor for malnutrition and sarcopenia risk with rapid weight loss
• Review and minimize medications that promote weight gain (antipsychotics, some antidepressants, glucocorticoids, some anticonvulsants)

Sibutramine note: While previously available and showing 4.5 kg greater weight loss than placebo at 1 year 4, this medication has been withdrawn from the U.S. market due to cardiovascular safety concerns 4

Special Population Considerations

• Pediatric patients ≥12 years: Orlistat is the only FDA-approved weight loss medication, showing modest efficacy 2
• Heart failure patients: Orlistat is the only medication studied in this population, showing 4.65 kg weight loss at 12 weeks with improved 6-minute walk distance 2
• Patients with fatty liver disease: GLP-1 receptor agonists may reduce hepatic steatosis beyond weight loss effects 6