Comparative Safety of GLP-1/GIP Co-Agonists Versus GLP-1 Receptor Agonists for Weight Loss in Patients with Obesity or Overweight: A Systematic Review.

Purpose: Tirzepatide, a dual GLP-1/GIP agonist, shows promise for weight loss, but its safety compared to GLP-1 receptor agonists requires (liraglutide, semaglutide) clarification for clinical decision-making. This systematic review evaluates their safety profiles in patients with obesity or overweight. Methods: We conducted a PRISMA-compliant systematic review (PROSPERO: CRD42024576314) of RCTs from PubMed, Embase, and Cochrane (inception to August 20, 2024). Adults with BMI ≥27 kg/m² (≥25 kg/m² for Asians) receiving GLP-1/GIP dual agonists (tirzepatide 10 or 15 mg) and GLP-1 receptor agonists (semaglutide 2.4 mg and liraglutide 3.0 mg) were included. Network meta-analysis (NMA) was conducted by using odds ratios with 95% CIs. Primary outcomes were adverse events (AEs) and serious AEs. NMA was performed using Stata 16.1. Results: This network meta-analysis included 19 randomized controlled trials (13,529 participants). Liraglutide 3.0 mg significantly increased the incidence of any adverse events (OR = 1.53-2.00) compared to semaglutide and tirzepatide, while tirzepatide showed a higher severe hypoglycemia risk (<54 mg/dL). Notably, GLP-1/GIP dual agonists demonstrated superior safety profiles in neoplasms (vs liraglutide: OR = 5.15 [1.28-20.74]; vs semaglutide: OR = 3.55 [1.10-11.54]) and respiratory infections/nasopharyngitis, suggesting enhanced anti-inflammatory effects. GLP-1 agonists had fewer diarrhea and injection-site reactions but higher abdominal pain/dyspepsia rates. Subgroup analyses further revealed that non-T2DM patients had a significantly higher incidence of adverse events compared to T2DM patients (P < 0.05), while no significant associations were observed with race, BMI, or treatment duration. Sensitivity analyses confirmed robustness and funnel plots indicated no publication bias. Conclusion: Liraglutide 3.0 mg was associated with higher overall adverse events, while tirzepatide (10 or 15 mg) showed increased severe hypoglycemia and injection-site reactions risk but superior anti-inflammatory and anti-neoplasm effects compared to GLP-1 mono-agonists. These findings highlight therapy-specific safety patterns critical for personalized treatment selection.