In an adult with obesity (BMI ≥ 30 kg/m²) eligible for chronic weight‑management therapy, how do Zepbound (tirzepatide) and Wegovy (semaglutide) compare in expected weight loss, dosing schedule, adverse‑effect profile, and which should be preferred as first‑line?

Zepbound (Tirzepatide) vs. Wegovy (Semaglutide) for Chronic Weight Management

Direct Recommendation

For adults with obesity (BMI ≥30 kg/m²) eligible for chronic weight management, tirzepatide (Zepbound) should be preferred as first-line therapy when maximum weight loss is the primary goal, achieving 20.9% weight loss versus semaglutide's 14.9%, though semaglutide (Wegovy) remains the definitive choice for patients with established cardiovascular disease due to proven cardiovascular outcome benefits. 1

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Weight Loss Efficacy Comparison

Tirzepatide demonstrates superior weight reduction across all metrics:

• Tirzepatide 15 mg weekly achieves 20.9% total body weight loss at 72 weeks, with approximately 40% of patients achieving ≥25% weight loss 1, 2
• Semaglutide 2.4 mg weekly produces 14.9% weight loss at 68 weeks, with 64.9% of patients achieving ≥10% weight loss 1
• The absolute difference is 6% greater weight loss with tirzepatide, representing a mean difference of 4.23 kg (95% CI: 3.22–5.25) 1, 3

Real-world data confirms trial findings: In a 2025 cohort study of 18,386 propensity-matched adults, tirzepatide users were 76% more likely to achieve ≥5% weight loss (HR 1.76), 154% more likely to achieve ≥10% loss (HR 2.54), and 224% more likely to achieve ≥15% loss (HR 3.24) compared to semaglutide 4. At 12 months, tirzepatide produced 6.9% greater weight reduction than semaglutide in real-world practice 4.

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Dosing Schedule & Administration

Both medications are administered as once-weekly subcutaneous injections, but differ in titration schedules: 1

Semaglutide (Wegovy) Titration:

• Week 1–4: 0.25 mg weekly 5
• Week 5–8: 0.5 mg weekly 5
• Week 9–12: 1.0 mg weekly 5
• Week 13–16: 1.7 mg weekly 5
• Week 17+: 2.4 mg weekly (maintenance) 5
• Total titration time: 16 weeks to reach maintenance dose 5

Tirzepatide (Zepbound) Titration:

• Starting dose: 5 mg weekly (FDA-approved) 1
• Escalation: Increase by 2.5 mg every 4 weeks based on tolerance 1
• Maximum dose: 15 mg weekly 1
• Total titration time: Variable, typically 12–16 weeks 1

Critical administration details: Both can be given at any time of day, with or without meals, but should be taken on the same day each week 5. No dose adjustment is required for renal impairment, including eGFR <30 mL/min/1.73 m² 1, 5.

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Adverse Effect Profile Comparison

Gastrointestinal effects dominate for both agents, with comparable overall tolerability:

Common Side Effects (Both Medications):

• Nausea: 17–22% (tirzepatide) vs. 18–40% (semaglutide) 1
• Diarrhea: 13–16% (tirzepatide) vs. 12% (semaglutide) 1
• Vomiting: 6–10% (tirzepatide) vs. 8–16% (semaglutide) 1
• Constipation: Common with both agents 1

These effects are typically mild-to-moderate, dose-dependent, and decrease over time with continued exposure. 1 Slow titration every 4 weeks minimizes gastrointestinal symptoms for both medications 1.

Serious Adverse Events (Identical for Both):

• Pancreatitis: Reported in clinical trials, though causality not definitively established 1
• Gallbladder disease: Cholelithiasis and cholecystitis occur with both; semaglutide shows 38% higher rate versus placebo 1
• Thyroid C-cell tumors: Both are absolutely contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 (MEN2) 1, 5

Real-world discontinuation rates: Semaglutide shows 34 more discontinuations per 1,000 patients versus placebo due to adverse events, primarily gastrointestinal 1. A 2024 head-to-head comparison found similar rates of gastrointestinal adverse events between tirzepatide and semaglutide 4.

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Cardiovascular & Cardiometabolic Benefits

Semaglutide holds a decisive advantage in proven cardiovascular protection:

• Semaglutide 2.4 mg reduces cardiovascular death, nonfatal MI, or nonfatal stroke by 20% (HR 0.80) in patients with established cardiovascular disease and BMI ≥27, even without diabetes 1
• The SELECT trial demonstrated this benefit in 17,600+ participants with prior MI, stroke, peripheral arterial disease, or revascularization 1
• Tirzepatide shows favorable cardiovascular safety (HR <1.0 for MACE-4 events) but lacks completed cardiovascular outcome trials proving event reduction 1

For broader cardiometabolic parameters, tirzepatide shows advantages:

• Greater waist circumference reduction 1
• Superior triglyceride reduction 1
• Better fasting glucose control 1
• Greater blood pressure reduction through multiple mechanisms 1

Clinical decision algorithm: For patients with established cardiovascular disease (prior MI, stroke, PAD, or revascularization), semaglutide 2.4 mg is the definitive first choice due to proven 20% MACE reduction 1. For patients without established CVD where maximum weight loss is the priority, tirzepatide 15 mg is preferred 1.

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Cost & Access Considerations

Both medications carry substantial costs:

• Semaglutide (Wegovy): ~$1,600 per 30-day supply 1
• Tirzepatide (Zepbound): ~$1,272 per 30-day supply 1

Insurance authorization may be challenging for both, particularly for obesity management without diabetes. 1 Tirzepatide faces more authorization barriers as the newer agent 1. Lifelong treatment is typically necessary—discontinuation results in regain of one-half to two-thirds of lost weight within 1 year 1.

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Mechanism of Action Differences

Tirzepatide's dual-receptor activation provides enhanced metabolic benefits:

• Tirzepatide is a dual GIP/GLP-1 receptor agonist, activating both glucose-dependent insulinotropic polypeptide (GIP) receptors and GLP-1 receptors 1
• This dual action produces synergistic effects on insulin response, glucagon suppression, delayed gastric emptying, appetite suppression, and increased energy expenditure 1
• Semaglutide is a selective GLP-1 receptor agonist with greater albumin affinity, resulting in prolonged action 1

Both medications work through central appetite suppression (hypothalamic and brainstem signaling), delayed gastric emptying, and glucose-dependent insulin secretion 1.

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Contraindications & Safety Monitoring

Absolute contraindications (identical for both):

• Personal or family history of medullary thyroid cancer 1, 5
• Multiple endocrine neoplasia syndrome type 2 (MEN2) 1, 5
• History of severe hypersensitivity reaction to the medication 5

Relative cautions:

• History of pancreatitis (use with caution; causality not established) 1
• Symptomatic gallbladder disease or gallstones 1
• Severe gastroparesis or GI motility disorders 1

Required monitoring:

• Every 4 weeks during titration: Weight, blood pressure, gastrointestinal tolerance, signs of pancreatitis or gallbladder disease 1
• Every 3 months after reaching maintenance dose: Weight stability, blood pressure, cardiovascular risk factors, medication adherence 1
• Treatment response evaluation at 12–16 weeks: Discontinue if <5% weight loss after 3 months at therapeutic dose 1, 5

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Perioperative Considerations

Both medications delay gastric emptying, creating aspiration risk during anesthesia:

• Discontinue semaglutide or tirzepatide at least 3 weeks (three half-lives) before elective surgery requiring anesthesia 1
• Retained gastric contents are documented even after extended fasting periods—24.2% of semaglutide users showed increased residual gastric content versus 5.1% of controls despite 10–14 day discontinuation and 12-hour fasting 1
• Consider gastric ultrasound pre-operatively to assess residual gastric contents 1

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Concomitant Medication Adjustments

When initiating either medication in patients on diabetes therapies:

• Reduce basal insulin by 20% immediately to prevent hypoglycemia 1
• Discontinue or reduce sulfonylureas by 50% due to increased hypoglycemia risk 1
• Do not combine with other GLP-1 receptor agonists or DPP-4 inhibitors—pharmacologically redundant and potentially harmful 1, 5

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Common Pitfalls to Avoid

1. Do not wait for multiple failed diet attempts before initiating pharmacotherapy in eligible candidates—early use improves outcomes 1
2. Do not skip slow titration—starting at maintenance doses markedly increases gastrointestinal adverse events and discontinuation rates 5
3. Do not prescribe to patients with personal/family history of MTC or MEN2—these are absolute contraindications 1, 5
4. Do not ignore perioperative aspiration risk—discontinue ≥3 weeks before elective surgery 1
5. Do not assume patients can discontinue after weight loss—lifelong treatment is typically necessary to maintain benefits 1
6. Do not overlook cardiovascular disease status—semaglutide is the only obesity medication with proven MACE reduction 1

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First-Line Recommendation Algorithm

Step 1: Screen for absolute contraindications (MTC, MEN2) 1, 5

Step 2: Assess cardiovascular disease status:

• If established CVD present (prior MI, stroke, PAD, revascularization) → Choose semaglutide 2.4 mg for proven 20% MACE reduction 1
• If no established CVD → Proceed to Step 3

Step 3: Prioritize treatment goal:

• If maximum weight loss is primary goal → Choose tirzepatide 15 mg (20.9% vs. 14.9% weight loss) 1
• If modest weight loss acceptable and patient prefers proven track record → Choose semaglutide 2.4 mg 1

Step 4: Combine with mandatory lifestyle modifications:

• 500-kcal daily deficit 1
• Minimum 150 minutes/week moderate-intensity physical activity 1
• Resistance training to preserve lean body mass 1

Step 5: Initiate slow titration per protocols above, monitoring every 4 weeks 1, 5

Step 6: Evaluate response at 12–16 weeks—discontinue if <5% weight loss 1, 5

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Both medications require lifelong use, must be combined with lifestyle modifications, and share similar safety profiles, but tirzepatide's superior weight loss makes it the preferred first-line choice for most patients without established cardiovascular disease. 1