Tirzepatide ranks highest for weight and waist reduction among GLP-1 and GLP-1/GIP receptor agonistsTirzepatide and Semaglutide Show Significant Weight Loss for Obesity

BACKGROUND/OBJECTIVES: The rapid rise in overweight and obesity worldwide underscores the need for comparative evidence on long-term pharmacotherapy. The recent introduction of a 7.2 mg maintenance dose of semaglutide warrants particular attention. We assessed the efficacy and safety of glucagon-like peptide-1 (GLP-1) and GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists-liraglutide, semaglutide, and tirzepatide-focusing on the incremental value of semaglutide 7.2 mg. SUBJECTS/METHODS: We conducted a systematic review and frequentist network meta-analysis (NMA) of phase 3 randomized controlled trials (RCTs) in adults (≥ 18 years) with body mass index (BMI) ≥ 25 kg/m², duration ≥ 52 weeks, comparing the above agents at approved weight management doses vs. placebo or each other (PROSPERO: CRD420251014401). Random effects models using the netmeta package estimated relative effects, ranking used P-scores. RESULTS: Twenty-four RCTs were included in the analysis, of which 23 were eligible for inclusion in the NMA. All active treatments reduced body weight, waist circumference, and BMI vs. placebo. Tirzepatide 15 mg ranked highest for weight and waist reduction across analyses based on P-scores. Semaglutide 7.2 mg ranked above semaglutide 2.4 mg for all efficacy endpoints based on P-scores; but the significant advantage in percentage bodyweight change was found only in the diabetes subgroup. Liraglutide 3.0 mg yielded the smallest weight loss. No significant between treatment differences were observed for serious adverse events (SAEs); however, tirzepatide was associated with higher risk of injection site reactions, and liraglutide with higher risks of any AEs and discontinuation due to AEs. Considerable heterogeneity was present for efficacy outcomes, with limited evidence of networkwide inconsistency; safety networks showed low to moderate heterogeneity. CONCLUSIONS: GLP-1 and GLP-1/GIP receptor agonists produce clinically meaningful weight loss vs. placebo over ≥ 1 year. Semaglutide 7.2 mg consistently ranks above 2.4 mg, but the average incremental benefit (~ 2-3% points) appears modest and should be interpreted in the context of limited statistically significant differences between doses, as well as balanced against considerations of tolerability and patient preferences. Further head-to-head trials and real world studies are warranted to refine dose selection and long-term safety.