Which is more effective for weight loss, semaglutide (glucagon-like peptide-1 receptor agonist) or tirzepatide (dual glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonist)?

Tirzepatide is Superior to Semaglutide for Weight Loss

Tirzepatide is more effective than semaglutide for weight loss, producing approximately 5% greater weight reduction at comparable doses, with tirzepatide 15mg achieving 20.9% weight loss compared to semaglutide 2.4mg achieving 14.9-16.0% weight loss. 1

Comparative Efficacy Data

Tirzepatide demonstrates superior weight loss efficacy compared to semaglutide based on the most recent and highest quality evidence:

• Tirzepatide weight loss outcomes 2, 1:

  • 5mg weekly: 15.0% at 72 weeks
  • 10mg weekly: 19.5% at 72 weeks
  • 15mg weekly: 20.9% at 72 weeks

• Semaglutide weight loss outcomes 1, 3:

  • 2.4mg weekly: 14.9-16.0% at 68 weeks
  • Mean difference compared to placebo: -12.1% at longest follow-up

A meta-analysis of RCTs including 12,371 adults with overweight or obesity without diabetes reported that 15mg weekly tirzepatide was associated with significantly greater weight loss compared to 2.4mg weekly subcutaneous semaglutide (mean difference, 5.1%; 95% CI, 0.6%-9.8%) 2.

Mechanism of Action Differences

The superior efficacy of tirzepatide can be attributed to its dual-hormone agonistic activity:

• Tirzepatide: Acts as both a GLP-1 receptor agonist AND a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist 2, 1
• Semaglutide: Acts only as a GLP-1 receptor agonist 4

This dual mechanism of tirzepatide appears to provide additive effects on weight loss beyond what can be achieved with GLP-1 receptor agonism alone.

Cost-Effectiveness Considerations

Tirzepatide provides better value for money than semaglutide for weight reduction:

• Cost needed to treat per 1% of body weight reduction 1:
  • Tirzepatide: $985 (95% CI: $908-$1075)
  • Semaglutide: $1845 (95% CI: $1707-$1989)

Safety Profile Comparison

Both medications have similar safety profiles, with gastrointestinal side effects being the most common:

• Common side effects for both medications 1, 5, 3:

  • Nausea
  • Vomiting
  • Diarrhea
  • Dyspepsia
  • Reflux

• Semaglutide adverse events 1:

  • 74.2% of users experience GI effects
  • 7.0% discontinue treatment due to adverse effects
  • 38% increased risk of serious adverse events compared to placebo

The gastrointestinal side effects for both medications are generally mild to moderate and often transient, typically subsiding within 1-2 days 6, 3.

Clinical Implications and Recommendations

Based on the most recent and highest quality evidence:

1. First-line choice: Tirzepatide (when available and affordable) due to its superior weight loss efficacy 1

2. Alternative option: Semaglutide if tirzepatide is unavailable or not tolerated 1

3. Dosing considerations:

   • Tirzepatide: Start low and gradually increase to target dose of 5-15mg weekly
   • Semaglutide: Start at 0.25mg weekly for weeks 1-4, increase to 0.5mg weekly for weeks 5-8, and gradually titrate to maintenance dose of 2.4mg weekly 1

4. Treatment monitoring:

   • Evaluate response at 12 weeks
   • Response criterion: ≥5% weight loss from initial body weight
   • Continue treatment indefinitely in responders to prevent significant weight regain 1

Important Caveats

• Individual response to these medications may vary
• Both medications require subcutaneous injection once weekly
• Insurance coverage and cost may significantly impact medication choice
• Treatment should be discontinued if 5% weight loss is not achieved at 12 weeks 1
• Both medications are contraindicated in pregnancy and in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 1