Obesity Drug of Choice for Weight Loss
For most patients seeking pharmacotherapy for obesity, GLP-1 receptor agonists—specifically semaglutide 2.4 mg weekly or tirzepatide—represent the drugs of choice due to their superior efficacy in achieving clinically meaningful weight loss (14-21%) compared to all other available options. 1, 2
Primary Recommendation: GLP-1 Receptor Agonists
First-Line Options by Efficacy
Tirzepatide (dual GIP/GLP-1 agonist) produces the greatest weight loss at 21% at 72 weeks, making it the most effective option currently available. 1, 2 This represents approximately 8-12% weight loss at 6 months, escalating to 15-21% by 72 weeks. 2
Semaglutide 2.4 mg weekly achieves 14.9% mean weight loss in non-diabetic patients with obesity, significantly outperforming other agents. 2 At 6 months, expect approximately 10-12% weight loss. 2
Liraglutide 3.0 mg daily produces 8.4 kg mean weight loss (approximately 5-8% body weight) at 56 weeks, with 63.2% of patients achieving ≥5% weight loss. 3, 1 This translates to approximately 4-6% weight loss at 6 months. 2
Indications for GLP-1 Agonists
Prescribe for patients with:
- BMI ≥30 kg/m², OR
- BMI ≥27 kg/m² with weight-related comorbidities (hypertension, type 2 diabetes, dyslipidemia, obstructive sleep apnea) 1, 2
Mechanism and Clinical Benefits
GLP-1 receptor agonists work by activating receptors in the hypothalamus and brainstem to suppress appetite, increase satiety, and delay gastric emptying. 2 Beyond weight loss, they reduce cardiovascular events in high-risk patients and improve metabolic parameters including HbA1c and lipid profiles. 2
Dosing Strategy
Start at low doses and titrate upward slowly to minimize gastrointestinal side effects:
- Liraglutide: Begin 0.6 mg daily, escalate by 0.6 mg weekly to target 3.0 mg daily 1
- Semaglutide: Follow manufacturer titration schedule to 2.4 mg weekly 2
- Tirzepatide: Titrate to 15 mg weekly for maximum effect 2
Discontinuation Criteria
Stop liraglutide if <4% body weight loss after 16 weeks of treatment. 1, 2 For other agents, discontinue if <5% weight loss after 12 weeks on maximum tolerated dose. 1
Critical Warnings
Common adverse effects include nausea, vomiting, diarrhea, and constipation—typically mild to moderate and diminishing over time. 1, 3 Weight regain occurs after discontinuation, necessitating long-term use for sustained benefit. 2
Contraindications include personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. 1
Alternative Agents When GLP-1s Are Unsuitable
Phentermine/Topiramate ER
Achieves 9.8-10.9% weight loss at 56 weeks, making it the second most effective option after GLP-1 agonists. 1 Typical dosing: start 3.75/23 mg daily for 2 weeks, increase to 7.5/46 mg daily, with further escalation to 15/92 mg as tolerated. 1
Contraindicated in patients with cardiovascular disease, uncontrolled hypertension, glaucoma, hyperthyroidism, or history of nephrolithiasis. 1 This is a Schedule IV controlled substance. 1
Naltrexone/Bupropion ER
Produces 4.8-6.1% weight loss at 56 weeks. 1 Ideal for patients with concomitant depression or those describing food cravings and addictive eating behaviors. 1 Also beneficial for patients attempting smoking cessation or alcohol reduction. 1
Avoid in patients with uncontrolled hypertension, seizure history, eating disorders (anorexia/bulimia), or recent MAOI use. 1 Carries black box warning for suicidality in young adults—monitor mood closely. 1
Phentermine Monotherapy
The most commonly prescribed and affordable obesity medication, producing 5.1-5.45% weight loss. 1 Typical dose: 15-37.5 mg once daily. 1, 4
FDA-approved only for short-term use (≤12 weeks), though longer use is common in practice. 1, 4 Absolutely contraindicated in patients with cardiovascular disease, uncontrolled hypertension, coronary artery disease, or history of substance abuse. 1, 4 This sympathomimetic agent should be avoided in patients with active cardiac disease despite recent data suggesting low risk of major adverse cardiac events. 1
Orlistat
The only obesity medication available across all regions globally, producing 3.1-4.0% weight loss at 1 year. 1 Dose: 120 mg three times daily with meals. 1
Best suited for patients with hypercholesterolemia and/or constipation who can limit dietary fat intake to <30% of calories. 1 Gastrointestinal side effects (steatorrhea, fecal urgency, oily spotting) are common and worsen with high-fat meals. 1
Recommend multivitamin supplementation (vitamins A, D, E, K) at bedtime or 2 hours after orlistat. 1 Administer levothyroxine 4 hours apart from orlistat due to decreased absorption. 1
Lorcaserin
Achieves 4.7-5.8% weight loss at 52 weeks. 1 Appropriate for patients reporting inadequate meal satiety. 1 Contraindicated with other serotonergic medications and in patients with cardiac valvular disease. 1
Special Populations
Patients with Type 2 Diabetes and Obesity
Prioritize GLP-1 receptor agonists (semaglutide, liraglutide, tirzepatide) or SGLT-2 inhibitors, which provide both glycemic control and weight loss. 1 Metformin produces approximately 3% weight loss and should be first-line for diabetes. 1
Avoid insulin, thiazolidinediones, sulfonylureas, and meglitinides—these cause weight gain of up to 10 kg over 36 months. 1
Patients with Cardiovascular Disease
GLP-1 receptor agonists reduce cardiovascular events and are preferred. 2 Absolutely avoid sympathomimetic agents (phentermine, phentermine/topiramate). 1 Orlistat and naltrexone/bupropion are safer alternatives. 1
β-blockers should be avoided as antihypertensive therapy in obesity due to weight gain promotion; if required, use selective β-blockers with vasodilating properties (carvedilol, nebivolol). 1
Asian Populations
Initiate pharmacotherapy at BMI >27 kg/m² or >25 kg/m² with complications, reflecting lower BMI thresholds for obesity-related risk. 1 Orlistat, liraglutide, and phentermine are most commonly available, though regional availability varies significantly. 1
Critical Clinical Pitfalls
Extended treatment is necessary for weight maintenance—short-term pharmacotherapy does not demonstrate long-term improvement in obesity-related complications, and weight regain is common upon discontinuation. 1, 2
Review all current medications for weight-gain potential: antidepressants (mirtazapine, amitriptyline), antipsychotics, antiepileptics, antihistamines, steroids, and certain antidiabetic agents all promote weight gain. 1 Consider alternatives when possible.
Medicare excludes coverage of FDA-approved obesity medications for obesity diagnosis alone, and global shortages of GLP-1 agonists currently exist. 1 Cost exceeds $1000/month for many agents without insurance coverage. 5
Pharmacotherapy should always accompany lifestyle interventions including reduced-calorie diet and increased physical activity—medications are adjuncts, not replacements. 1