Latest Weight Loss Medications
Tirzepatide is the most effective FDA-approved weight loss medication currently available, producing 21% weight loss at 72 weeks, followed by semaglutide 2.4 mg achieving 15-17% weight loss at 1 year. 1, 2
First-Line Medication Hierarchy
The treatment algorithm for maximum weight loss prioritizes medications in the following order based on efficacy 1, 2:
- Tirzepatide (dual GIP/GLP-1 agonist) - 21% weight loss at 72 weeks, making it the most effective option 3, 1, 2
- Semaglutide 2.4 mg weekly - 15-17% weight loss at 1 year with proven cardiovascular event reduction 1, 2, 4, 5
- Liraglutide 3.0 mg daily - 8-10% weight loss with established cardiovascular safety 1, 2, 4
Additional FDA-Approved Long-Term Options
Beyond the GLP-1 agonists, several other medications are approved for chronic weight management 1, 2:
- Phentermine/topiramate extended-release - 6.6% weight loss at 1 year, but contraindicated in cardiovascular disease and requires adequate contraception due to teratogenic effects 1, 4
- Naltrexone-bupropion - 4.8% weight loss at 56 weeks 2
- Orlistat - Modest 2.9 kg (approximately 3.1%) weight loss at 12 months with added LDL cholesterol reduction benefit, requires fat-soluble vitamin supplementation 1, 2, 4
Short-Term Medication
- Phentermine monotherapy - 3.75-5.1% weight loss at 28 weeks, approved only for short-term use (a few weeks), contraindicated in coronary artery disease, uncontrolled hypertension, and cardiovascular disease 1, 6
Patient Selection Criteria
Pharmacotherapy is indicated for 1, 4:
- BMI ≥30 kg/m² regardless of comorbidities
- BMI ≥27 kg/m² with weight-related comorbidities (type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea)
- Modified thresholds for Asian populations: BMI >27 kg/m² or >25 kg/m² with complications 1
Special Population Considerations
For patients with type 2 diabetes: Prioritize GLP-1 agonists (tirzepatide, semaglutide, liraglutide) for dual glycemic control and weight-independent cardiometabolic advantages 1, 2, 4
For patients with cardiovascular disease: Avoid sympathomimetic agents (phentermine, phentermine/topiramate) and select semaglutide 2.4 mg for proven cardiovascular event reduction or liraglutide for cardiovascular safety 1, 4
For patients with heart failure: 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
Monitoring and Discontinuation Criteria
- Assess response monthly for the first 3 months, then quarterly 4
- Discontinue medication if weight loss is <5% of total body weight after 12 weeks (3 months) on maximally tolerated dosage 1, 4
- All medications require indefinite continuation for sustained benefit; weight regain occurs with discontinuation 1, 2, 4
Critical Implementation Points
Always combine medications with lifestyle modifications including reduced-calorie diet and at least 150 minutes of moderate-intensity aerobic exercise weekly 2, 4
Common pitfalls to avoid:
- Never prescribe weight loss medications to patients with BMI <25 kg/m² 1
- Avoid sympathomimetic agents in patients with cardiovascular disease or uncontrolled hypertension 1, 4
- Review and minimize medications that promote weight gain (antipsychotics, mirtazapine, amitriptyline, glyburide, insulin, glucocorticoids) 4
- GLP-1 agonists are contraindicated in pregnancy and may increase risk for malnutrition and sarcopenia 4
Comparison to Older Guidelines
The 2005 American College of Physicians guidelines recommended sibutramine (4.5 kg weight loss), orlistat (2.89 kg), phentermine (3.6 kg), and diethylpropion (3.0 kg) 3. The newer GLP-1 agonists and tirzepatide represent a paradigm shift, achieving 3-7 times greater weight loss than these older agents and providing cardiovascular benefits not demonstrated with previous medications 3, 1, 2.