BACKGROUND AND PURPOSE:

• The efficacy of both tirzepatide (dual GIP and GLP-1 receptor agonist) and semaglutide (selective GLP-1 receptor agonist) for the treatment of obesity is well established
• It is not clear whether one is more efficacious or safer than the other
• Aronne et al. (NEJM, 2025) assessed whether tirzepatide or semaglutide was superior to the other for the treatment of obesity without type 2 diabetes

METHODS:

• Phase 3b, open-label, controlled trial
  • 32 sites in the US and Puerto Rico
• Participants
  • Adult participants with obesity
  • No type 2 diabetes
• Interventions
  • Maximum tolerated dose of tirzepatide (10 mg or 15 mg)
  • Maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg)
• Study design
  • Medications administered subcutaneously once weekly for 72 weeks
  • 1:1 randomization
  • If patients stopped due to side effects were encouraged to remain in the trial for follow-up
  • Nutritional and physical activity counseling provided to all participants 
• Primary outcome
  • Least-squares mean percent change in weight from baseline to week 72
• Secondary outcomes
  • Weight reductions of at least 10% | 15% | 20% | 25%
  • Change in waist circumference from baseline to week 72

RESULTS:

• 751 participants
• The percent change in weight at week 72 was greater in the tirzepatide group (P<0.001)
  • Tirzepatide: −20.2% (95% CI, −21.4 to −19.1)
  • Semaglutide: −13.7% (95% CI, −14.9 to −12.6)
• Mean change in waist circumference was also greater with tirzepatide (P<0.001)
  • Tirzepatide: −18.4 cm (95% CI, −19.6 to −17.2)
  • Semaglutide: −13.0 cm (95% CI, −14.3 to −11.7)
• Participants in the tirzepatide group were more likely than those in the semaglutide group to have weight reductions of at least 10%, 15%, 20%, and 25%
• Most common adverse events in both treatment groups were gastrointestinal
  • Most were mild to moderate
  • Most occurred during dose escalation

CONCLUSION:

• In the setting of obesity but no diabetes, a 20.2% weight reduction was seen with tirzepatide vs a 13.7% reduction with semaglutide
• Adverse events were similar for tirzepatide and semaglutide
• The authors state

In this trial, treatment with tirzepatide, a dual GIP and GLP-1 receptor agonist, was superior to treatment with semaglutide, a selective GLP-1 receptor agonist, with respect to reduction in body weight and waist circumference

Learn More – Primary Sources:

Tirzepatide as Compared with Semaglutide for the Treatment of Obesity