Which appetite‑suppressing pharmacologic agents are appropriate for an adult with obesity (BMI ≥ 30 kg/m², or BMI ≥ 27 kg/m² with hypertension, type 2 diabetes, or dyslipidaemia), and what are their recommended dosing, titration schedules, and contraindications?

Appetite Suppressant Medications for Adult Obesity

For adults with obesity (BMI ≥30 kg/m²) or overweight with comorbidities (BMI ≥27 kg/m² with hypertension, type 2 diabetes, or dyslipidemia), GLP-1 receptor agonists—specifically semaglutide 2.4 mg weekly or tirzepatide 15 mg weekly—are the definitive first-line pharmacologic options, achieving 15–21% weight loss and providing cardiovascular protection that older appetite suppressants cannot match. 1, 2

Patient Eligibility Criteria

Initiate anti-obesity medication when:

• BMI ≥30 kg/m² without additional requirements 1
• BMI ≥27 kg/m² with at least one weight-related comorbidity: hypertension, type 2 diabetes, or dyslipidemia 1
• Inadequate response to lifestyle modifications (reduced-calorie diet, ≥150 min/week physical activity) after 3–6 months 1, 3

Absolute contraindications for GLP-1 receptor agonists:

• Personal or family history of medullary thyroid carcinoma 1, 2
• Multiple endocrine neoplasia type 2 (MEN 2) 1, 2
• Pregnancy or breastfeeding 2

First-Line Pharmacotherapy: GLP-1 Receptor Agonists

Semaglutide 2.4 mg (Wegovy)

Dosing & Titration:

• Week 1–4: 0.25 mg subcutaneously once weekly 1, 2
• Week 5–8: 0.5 mg weekly 1, 2
• Week 9–12: 1.0 mg weekly 1, 2
• Week 13–16: 1.7 mg weekly 1, 2
• Week 17+: 2.4 mg weekly (maintenance) 1, 2

Expected Efficacy:

• Mean weight loss: 14.9% at 68 weeks 1, 2
• 64.9% of patients achieve ≥10% weight loss 2
• Cardiovascular benefit: 20% reduction in CV death, MI, or stroke in patients with established CVD 1, 2

Monitoring:

• Assess monthly during first 3 months for GI tolerance, weight loss, blood pressure 1, 4
• Evaluate at 12–16 weeks: discontinue if <5% weight loss 1, 4
• After maintenance dose: monitor every 3 months for weight, BP, CV risk factors 1, 2

Tirzepatide 15 mg (Zepbound/Mounjaro)

Dosing & Titration:

• Week 1–4: 2.5 mg subcutaneously once weekly 2, 4
• Week 5–8: 5 mg weekly 2, 4
• Week 9–12: 10 mg weekly 2, 4
• Week 13+: 15 mg weekly (maximum approved dose) 2, 4

Expected Efficacy:

• Mean weight loss: 20.9% at 72 weeks 1, 2
• Superior to semaglutide by 6% absolute weight loss 2
• Approximately 40% achieve ≥25% weight loss 2, 4

Choose tirzepatide over semaglutide when:

• Maximum weight loss is the primary goal (BMI >35 kg/m²) 2
• Patient requires superior HbA1c reduction (if diabetic) 2

Choose semaglutide over tirzepatide when:

• Established cardiovascular disease is present (proven MACE reduction) 1, 2

Concomitant Medication Adjustments

When initiating GLP-1 receptor agonists:

• Reduce basal insulin by 20% to prevent hypoglycemia 1, 2
• Discontinue or reduce sulfonylureas by 50% 1, 2
• Stop all DPP-4 inhibitors (no additional benefit) 2

For patients on antihypertensives:

• Monitor BP closely; weight loss may require dose reduction 1, 2

Second-Line Options (When GLP-1 RAs Are Unavailable or Contraindicated)

Phentermine (Short-Term Only)

FDA-Approved Dosing:

• 15–37.5 mg orally once daily, approximately 2 hours after breakfast 5
• FDA-approved for ≤12 weeks only (not for chronic weight management) 1, 5

Expected Efficacy:

• Mean weight loss: 3.63% vs. placebo 1
• 4.12× more likely to achieve 5% weight loss 1

Contraindications:

• History of cardiovascular disease (coronary artery disease, stroke, arrhythmias, uncontrolled hypertension) 5
• Hyperthyroidism 5
• Glaucoma 5
• Agitated states or history of drug abuse 5
• Within 14 days of MAOI use 5

Monitoring:

• Blood pressure and heart rate periodically 1, 5

Phentermine/Topiramate ER (Qsymia)

Expected Efficacy:

• Approximately 9% total body weight loss with 15 mg/92 mg dose 4

Contraindications:

• Avoid in cardiovascular disease 4

Naltrexone-Bupropion (Contrave)

Expected Efficacy:

• 3.01% weight reduction 2
• Higher discontinuation rates due to neuropsychiatric adverse effects 2

Orlistat (Xenical)

Dosing:

• 120 mg orally three times daily with meals 4, 6

Expected Efficacy:

• Mean weight loss: 2.9 kg at 12 months 4

Adverse Effects:

• Abdominal pain, diarrhea, oily spotting, reduced absorption of fat-soluble vitamins 4

Mandatory Lifestyle Interventions

All pharmacotherapy must be combined with:

• Daily caloric deficit of 500–1,000 kcal 1, 6, 3
• Minimum 150–300 min/week moderate-intensity aerobic activity 1, 6, 3
• Resistance training ≥2 times/week 1, 6
• Behavioral counseling and structured lifestyle support 1, 6

Treatment Discontinuation Criteria

Stop medication if:

• <5% weight loss after 3 months at therapeutic dose 1, 4, 6
• Persistent severe abdominal pain (pancreatitis concern) 1, 2
• Right upper quadrant pain with fever (cholecystitis concern) 2
• Significant safety or tolerability issues 1

Special Populations

Renal Impairment:

• Semaglutide, liraglutide, tirzepatide: no dose adjustment required across all CKD stages, including eGFR <30 mL/min/1.73 m² 2
• Phentermine: limit to 15 mg daily for severe renal impairment (eGFR 15–29 mL/min/1.73 m²) 5

Type 2 Diabetes:

• Prioritize GLP-1 receptor agonists for dual benefits: weight loss and glycemic control 1
• Weight loss is typically lower in diabetic patients (4–6.2%) vs. non-diabetic (6.1–17.4%) 2

Established Cardiovascular Disease:

• Semaglutide 2.4 mg is the definitive choice (26% MACE reduction) 1, 2

Common Pitfalls to Avoid

• Do not use pharmacotherapy as monotherapy—it must be paired with lifestyle modification throughout treatment 1, 4, 6
• Do not continue ineffective treatment beyond 12 weeks at maintenance dose if <5% weight loss 1, 4
• Do not prescribe phentermine for chronic weight management—FDA approval is for ≤12 weeks only 1, 5
• Do not combine GLP-1 receptor agonists with DPP-4 inhibitors—no additional benefit 2
• Do not delay GLP-1 RA initiation in eligible patients with CVD or CKD—early use improves outcomes 2

Cost Considerations

• Semaglutide 2.4 mg: approximately $1,619 per 30-day supply 2
• Tirzepatide: approximately $1,272 per 30-day supply 2, 4
• Lifelong treatment is typically necessary to maintain weight loss 1, 2

When to Consider Metabolic Surgery

Refer for bariatric surgery when:

• BMI ≥40 kg/m² regardless of comorbidities 1, 6
• BMI ≥35 kg/m² with severe obesity-related complications after pharmacotherapy failure 1, 6
• Expected weight loss: 25–30% of initial body weight 6