What is the drug of choice for weight loss?

Drug of Choice for Weight Loss

Semaglutide 2.4 mg weekly (or tirzepatide) is the drug of choice for weight loss in most patients, offering superior efficacy with 15-21% weight loss and proven cardiovascular benefits. 1

First-Line Recommendation: GLP-1 Receptor Agonists

GLP-1 receptor agonist-based medications represent the most effective pharmacotherapy for obesity management. The American College of Cardiology identifies semaglutide 2.4 mg weekly or tirzepatide as the preferred first-line choice due to superior efficacy and cardiovascular benefits. 1 These agents achieve substantially greater weight loss compared to all other available medications:

• Semaglutide 2.4 mg weekly produces 15-21% total body weight loss 1
• Liraglutide 3.0 mg daily achieves 5.4% mean weight loss at 56 weeks 1
• Tirzepatide (dual GIP/GLP-1 RA) demonstrates comparable or superior efficacy to semaglutide 2

Beyond weight reduction, these medications provide additional cardiometabolic benefits including reductions in lipids, blood pressure, and glucose levels. 2 Critically, semaglutide 2.4 mg has demonstrated cardiovascular benefits in persons with obesity, directly impacting mortality and morbidity. 2

Dosing and Administration

Liraglutide requires dose escalation from 0.6 mg daily, increasing by 0.6 mg weekly up to the target dose of 3.0 mg daily. 1 Semaglutide is administered as a once-weekly subcutaneous injection at 2.4 mg. 1 Slow up-titration minimizes the primary adverse effects—gastrointestinal symptoms that are typically transient and occur during dose escalation. 2

Second-Line Options

Phentermine/Topiramate ER

When GLP-1 agonists are contraindicated or unavailable, phentermine/topiramate ER represents the next best alternative, achieving 6.6% mean weight loss at 1 year. 1 This fixed-dose combination targets multiple pathways and also improves cardiovascular risk factors including lipids and blood pressure. 2

Critical contraindications include: 1

• Cardiovascular disease
• Pregnancy
• Glaucoma (untreated closed-angle)
• Hyperthyroidism

Important monitoring requirements: 1

• Blood pressure and heart rate monitoring
• Monthly pregnancy testing for women of reproductive age

Adverse effects include increased heart rate, mood and sleep disorders, impaired cognitive function, and increased creatinine. 2

Third-Line: Orlistat

Orlistat (120 mg three times daily with meals) blocks approximately 30% of dietary fat absorption, achieving modest 3.1% mean weight loss at 1 year. 1 This medication has several specific advantages:

• No systemic absorption, making it the safest option for patients with cardiovascular contraindications to sympathomimetic agents 1
• Budget-friendly option for patients with limited financial resources 1
• Demonstrated reduction in progression to type 2 diabetes in prediabetic populations 2
• 10% reduction in LDL-cholesterol independent of weight loss 3

Mandatory supplementation: Fat-soluble vitamins (A, D, E, K) must be supplemented due to malabsorption. 1 Gastrointestinal side effects (oily spotting, fecal urgency) are significant but can be minimized when patients consume <30% of calories from fat. 4

Patient Selection Criteria

Pharmacotherapy is indicated for: 1

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

Efficacy Assessment and Duration

Assess response monthly for the first 3 months, then quarterly. 1 Discontinue or change medication if <5% weight loss is achieved after 3 months at therapeutic dose. 1

Critical principle: Continue medication beyond reaching weight loss goals to maintain benefits, as obesity is a chronic disease requiring indefinite treatment. 1 This represents a fundamental shift from older short-term approaches.

Special Populations and Pitfalls

Avoid in Patients with Kidney Disease

For patients with minimal change disease or active nephrotic syndrome, orlistat is the only appropriate choice due to its lack of systemic absorption. 3 GLP-1 agonists and sympathomimetic agents (phentermine) should be avoided until the disease is in remission. 3

Critical Medication Interactions to Avoid

• Never combine phentermine with other weight loss medications 1
• Avoid β-blockers as antihypertensives in patients with obesity, as they promote weight gain and prevent weight loss 1, 5
• Phentermine is contraindicated within 14 days of MAO inhibitors due to hypertensive crisis risk 5

Short-Term vs. Long-Term Use

Phentermine monotherapy is FDA-approved only for short-term use (a few weeks) 6, though it is commonly prescribed off-label for longer durations, achieving 6.0 kg weight loss at 28 weeks with 46% of patients achieving ≥5% weight loss. 5 However, given the availability of more effective long-term options with proven cardiovascular benefits, phentermine should be reserved for situations where first-line agents are unavailable or contraindicated.

Why GLP-1 Agonists Are Superior

The magnitude of weight loss matters significantly for health outcomes. Large weight loss (≥10%) provides major beneficial impacts on obesity-related complications including improvements in type 2 diabetes, hypertension, glucose metabolism, cardiovascular risk factors, reduced cancer risk, and improvements in knee osteoarthritis, sleep apnea, and fertility. 7 Only GLP-1 receptor agonists consistently achieve this magnitude of weight loss through pharmacotherapy alone, making them the clear drug of choice for most patients seeking meaningful improvements in morbidity, mortality, and quality of life.