What medications are recommended for weight loss?

Weight Loss Medications

For patients with BMI ≥30 kg/m² or BMI ≥27 kg/m² with weight-related comorbidities, tirzepatide is the first-line medication for weight loss, achieving 21% weight reduction at 72 weeks, followed by semaglutide 2.4 mg weekly (15-17% weight loss) as the second choice. 1, 2

Medication Selection Algorithm

First-Line Options (in order of efficacy):

1. Tirzepatide (dual GIP/GLP-1 agonist)

• Most effective FDA-approved option with 21% weight loss at 72 weeks 1
• Provides additional glycemic benefits in patients with type 2 diabetes 1
• Requires continuation for sustained benefit; discontinuation leads to weight regain 1

2. Semaglutide 2.4 mg weekly

• Achieves 8-21% weight reduction with superior cardiovascular benefits 1, 2
• Preferred in patients with established cardiovascular disease 1
• Demonstrated cardiovascular safety in SUSTAIN 6 trial 3

3. Liraglutide 3.0 mg daily

• Produces 8-21% weight loss with proven cardiovascular safety 1
• Alternative to semaglutide when weekly injections are not preferred 4, 2
• Mean weight loss of 5.4% at 56 weeks compared to placebo 4

Alternative First-Line Options:

4. Phentermine-topiramate extended release

• Achieves 6.6% weight loss at 1 year compared to placebo 4
• Contraindicated in patients with cardiovascular disease, uncontrolled hypertension, glaucoma, and substance use disorder history 4, 1
• Requires dose escalation from 3.75/23 mg to maximum 15/92 mg daily 4

5. Naltrexone-bupropion

• Produces 4.8% weight loss at 56 weeks 4, 1
• Safer cardiovascular profile than sympathomimetic agents 4
• Not a controlled substance 4

6. Orlistat 120 mg three times daily

• Modest weight loss of 2.9 kg at 12 months 1
• Only FDA-approved medication for children ≥12 years old 1
• Preferred option in patients with heart failure (4.65 kg weight loss at 12 weeks with improved 6-minute walk distance) 1
• Provides LDL cholesterol reduction beyond weight loss alone 1
• Available over-the-counter at lower dose (Alli) 2
• Side effects include fecal urgency, oily spotting, and flatulence 4

Short-Term Option:

7. Phentermine monotherapy

• Produces 3.75% weight loss but approved only for short-term use 1
• Avoid in coronary artery disease, uncontrolled hypertension, glaucoma, and substance use disorder 1
• Schedule IV controlled substance 4

Special Population Considerations

Patients with Type 2 Diabetes:

• Prioritize GLP-1 agonists (semaglutide, liraglutide) or tirzepatide for glycemic benefits and weight-independent cardiometabolic advantages 1
• Metformin produces approximately 3% weight loss, with doses >1500 mg showing greatest efficacy 1
• SGLT-2 inhibitors produce clinically meaningful weight loss with added cardiometabolic benefits 1

Patients with Cardiovascular Disease:

• Avoid sympathomimetic agents (phentermine, phentermine-topiramate) 4
• Use lorcaserin, orlistat, or GLP-1 agonists as safer alternatives 4
• Semaglutide demonstrated cardiovascular safety and reduced MACE in SUSTAIN 6 trial 3

Patients with Heart Failure:

• Orlistat is the only medication studied in this population 1

Pediatric Patients (≥12 years):

• Orlistat is the only FDA-approved option with modest efficacy 1

Implementation Requirements

Indications:

• BMI ≥30 kg/m² without comorbidities 4, 2
• BMI ≥27 kg/m² with weight-related comorbidities (hypertension, type 2 diabetes, dyslipidemia, obstructive sleep apnea) 4, 2

Mandatory Concurrent Interventions:

• All medications must be combined with reduced-calorie diet, increased physical activity, and behavioral counseling 4, 1, 2
• High-intensity lifestyle intervention (≥14 sessions in 6 months) 4
• Calorie restriction of 1,200-1,500 kcal/day for women, 1,500-1,800 kcal/day for men 4

Monitoring Protocol:

• Assess efficacy and safety monthly for first 3 months, then quarterly thereafter 4, 2
• Discontinue or change medication if <5% weight loss after 12 weeks 4, 2
• Continue medication beyond reaching weight loss goals to maintain health benefits 2

Critical Pitfalls to Avoid

1. Medication discontinuation:

• Sudden discontinuation results in weight regain and worsening cardiometabolic risk factors 2
• Medications require continuation for sustained benefit 1

2. Concomitant weight-promoting medications:

• Review and address medications that promote weight gain (antipsychotics, some antidepressants, glucocorticoids, β-blockers) 2

3. Monotherapy without lifestyle modification:

• Never use medications without concurrent lifestyle interventions 2
• Pharmacotherapy alone is insufficient 4

4. Inadequate treatment intensity:

• Low-intensity interventions produce inferior results compared to high-intensity programs (>1 session per month for first 3 months) 4

5. Insurance barriers:

• Medicare currently excludes coverage of FDA-approved anti-obesity medications for obesity alone 2
• Global shortages of GLP-1 receptor agonists may affect availability 2

Expected Outcomes

Weight Loss Hierarchy:

• Tirzepatide: 21% 1
• Semaglutide: 15-17% 1
• Liraglutide: 8-10% 1
• Phentermine-topiramate: 6.6% 1
• Naltrexone-bupropion: 4.8% 1
• Orlistat: 2.9 kg 1

Health Benefits:

• 3-5% weight loss produces clinically meaningful reductions in triglycerides, blood glucose, HbA1c, and risk of type 2 diabetes 4
• Greater weight loss (≥10%) improves blood pressure, LDL-C, HDL-C, and reduces need for medications to control blood pressure, glucose, and lipids 4, 5