What is the first-line medication for weight loss?

First-Line Weight Loss Medication

Semaglutide 2.4 mg weekly or tirzepatide is the preferred first-line medication for most patients seeking weight loss pharmacotherapy, based on superior efficacy and cardiovascular benefits. 1

Patient Selection Criteria

Pharmacotherapy is indicated for patients meeting the following BMI thresholds 1, 2:

• BMI ≥30 kg/m² (obesity), OR
• BMI ≥27 kg/m² with weight-related comorbidities including:
  • Type 2 diabetes
  • Hypertension
  • Dyslipidemia
  • Obstructive sleep apnea

First-Line Medication Options by Clinical Context

Preferred First-Line: GLP-1 Agonists

Semaglutide 2.4 mg weekly or tirzepatide should be prioritized for most patients due to superior efficacy and cardiovascular benefits. 1 However, these newer agents may face insurance barriers or cost limitations in real-world practice.

Liraglutide 3.0 mg (Saxenda) is an alternative GLP-1 agonist with established efficacy:

• Mean weight loss: 5.4% at 56 weeks 1
• Requires dose escalation: Start 0.6 mg daily, increase by 0.6 mg weekly up to 3.0 mg 1

Alternative First-Line: Phentermine/Topiramate ER (Qsymia)

When GLP-1 agonists are contraindicated, unavailable, or unaffordable, phentermine/topiramate ER is the next preferred option:

• Mean weight loss: 6.6% at 1 year 1
• Fixed-dose combination targeting multiple pathways 3
• Dosing algorithm: Start 3.75/23 mg daily for 14 days → 7.5/46 mg daily → assess at 12 weeks 3
• Discontinue if <3% weight loss after 12 weeks at 7.5/46 mg, or <5% weight loss after 12 weeks at 15/92 mg 3, 4

Critical contraindications for phentermine/topiramate ER 1, 4:

• Cardiovascular disease
• Pregnancy (Category X - requires monthly pregnancy testing)
• Glaucoma
• Hyperthyroidism

Budget-Friendly First-Line: Orlistat

Orlistat (Xenical 120 mg or OTC Alli 60 mg) is the most accessible option:

• Mean weight loss: 3.1% at 1 year 1
• Blocks ~30% of dietary fat absorption 3, 5
• Dosing: 120 mg three times daily with each main meal containing fat 3
• Requires multivitamin supplementation (fat-soluble vitamins A, D, E, K) taken 2 hours before or after orlistat 3, 1

Orlistat is particularly appropriate for patients with 3:

• Obesity with constipation (gastrointestinal effects may be beneficial)
• Cardiovascular contraindications to sympathomimetic agents
• Limited financial resources (available OTC)

Off-Label First-Line: Phentermine Monotherapy

Phentermine monotherapy remains the most commonly prescribed anti-obesity medication despite FDA approval only for short-term use (3 months) 3:

• Weight loss: 6.0 kg at 28 weeks 3, 6
• 46% achieve ≥5% weight loss; 20.8% achieve ≥10% weight loss 3, 6
• Dosing: 15-37.5 mg orally once daily in the morning 3, 2
• Many practitioners prescribe off-label for longer durations 3

Appropriate candidates for phentermine 3, 6:

• Younger patients without cardiovascular disease
• No active/unstable coronary disease or uncontrolled hypertension
• No anxiety or insomnia (may be exacerbated)
• Need for appetite suppression

Absolute contraindications 2:

• History of cardiovascular disease (coronary artery disease, stroke, arrhythmias, CHF, uncontrolled hypertension)
• Within 14 days of MAOI use
• Hyperthyroidism
• Glaucoma
• History of drug abuse
• Pregnancy/nursing

Monitoring and Efficacy Assessment

Assessment schedule 1:

• Monthly for first 3 months
• Quarterly thereafter
• Discontinue or change medication if <5% weight loss after 3 months at therapeutic dose

Critical principle: Continue medication beyond reaching weight loss goals to maintain benefits, as obesity is a chronic disease requiring indefinite treatment. 1

Common Pitfalls to Avoid

1. Do not combine phentermine with other weight loss medications - safety and efficacy not established, particularly with serotonergic agents (SSRIs) 2

2. Do not exceed recommended phentermine doses when tolerance develops - discontinue rather than escalate 2

3. Avoid β-blockers (atenolol, metoprolol, nadolol, propranolol) as antihypertensives in patients with obesity - they promote weight gain 3, 6

4. Monitor blood pressure and heart rate with sympathomimetic agents (phentermine, phentermine/topiramate) 3, 6

5. Ensure monthly pregnancy testing for women of reproductive age on phentermine/topiramate ER due to teratogenicity risk 4

6. Adjust phentermine dosing in renal impairment: Maximum 15 mg daily for eGFR 15-29 mL/min/1.73 m²; avoid if eGFR <15 mL/min/1.73 m² 2